WO2025090967A1

WO2025090967A1 - Pharmacological agonist of klf2 reduces osteoclast differentiation, inflammation, and covid

Info

Publication number: WO2025090967A1
Application number: PCT/US2024/053120
Authority: WO
Inventors: Hiranmoy Das; Bhaskar Das
Original assignee: Texas Tech University TTU; Long Island University; Texas Tech University System
Current assignee: Texas Tech University TTU; Long Island University; Texas Tech University System
Priority date: 2023-10-27
Filing date: 2024-10-25
Publication date: 2025-05-01
Anticipated expiration: 2026-04-27
Also published as: WO2025090967A9

Abstract

Provided herein are compositions and methods for treating musculoskeletal disorder such as arthritis, rheumatoid arthritis, osteoporosis, wound healing, corneal epithelial dystrophies and injuries, and cytokine storm with a molecule of formula: and one or more pharmaceutical acceptable excipients or salts; and methods for preventing and/or treating musculoskeletal disorder such as arthritis, rheumatoid arthritis, osteoporosis, wound healing, corneal epithelial dystrophies and injuries, and cytokine storm triggered by a coronavirus 2 (SARS-CoV-2) infection or fibrosis in a subject.

Description

PHARMACOLOGICAL AGONISTS OF KLF2 REDUCES OSTEOCLAST DIFFERENTIATION, INFLAMMATION, WOUND HEALING, AND COVID CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial Nos. 63/593,641 and 63/593,670, both filed Oct.27, 2023, the entire contents of each are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates in general to the field of differentiation and inflammation, and more particularly, to a pharmacological agonist of KLF2 that reduces osteoclast differentiation and inflammation, wound healing, and to prevent the cytokine storm associated with inflammation, e.g., during infection with coronavirus 2 (SARS-CoV-2) infection. STATEMENT OF FEDERALLY FUNDED RESEARCH [0003] This invention was made with government support under AR068279 awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC [0004] Not applicable. BACKGROUND OF THE INVENTION [0005] Without limiting the scope of the invention, its background is described in connection with inflammatory diseases and with coronavirus 2 (SARS-CoV-2) infection. [0006] Rheumatoid Arthritis (RA) is a complex autoimmune disease afflicting more than 27 million individuals in the U.S. alone. It is known that inflammatory cytokines play an important role in RA development and pathogenesis. Biological therapies targeting these have revolutionized RA therapy, however, 50% of patients are non-responders to these therapies. [0007] The SARS-CoV-2 virus is known to trigger a cytokine storm, which is characterized by the production of excessive amounts of pro-inflammatory factors at both the local and systemic levels (5). The cytokine storm is one of the most prevalent causes of multi-organ failure, and it has been associated with severity of the disease, as well as the development of acute respiratory distress syndromes (ARDS) and cardiac injury in patients (6). In fact, the severity of infection with SARS-CoV-2 has been positively correlated with the presence of specific cytokines, such as, arginase I (Arg1), hypoxia-inducible factor (HIF-1) α, interleukin (IL)-4R, IL-6, IL-10, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)3, MMP9, and MMP13 (7). Whereas IL-4 stimulates T-helper-2 (Th2) lymphocytes, which activate M2 macrophages that then secrete transforming growth factor beta (TGF-β) (8). MMP9 also induces the development of fibrosis by activating TGF-β (9). TGF-β is the main cytokine responsible for the augmented matrix deposition in the lung of people suffering from idiopathic pulmonary fibrosis (IPF), mainly because of fibroblast recruitment and transformation (10). TGF-β can activate cells using a variety of downstream signaling pathways, including extracellular signal-related protein kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK) (11). The PI3K/Akt/mTOR pathways affect the production of pro-inflammatory cytokines, which also affect the immune response (12). Therapeutic methods designed to inhibit harmful immune responses via PI3K/Akt opened one of the avenues for the treatment of severe COVID pathogenesis (13). The abnormal signaling pathway between PI3K and Akt contributes to the increased production of reactive oxygen species (ROS) by modulating mitochondrial bioenergetics, as well as indirectly producing ROS through metabolic processes. There is a strong correlation between COVID severity and overactivation of the PI3K/Akt/mTOR pathway (14). [0008] Existing COVID-19 treatments are limited to three antiviral therapies. Nirmatrelvir is administered to adults and children 12 and older within 5 days of symptoms (oral tablets at home). Remdesivir is administered to adults and children within 7 days of symptoms (IV infusions at healthcare facility for 3 consecutive days). Molnupiravir is administered to adults within 5 days of symptoms (oral tables at home). To date, the virus has shown an ability to mutate in a way that makes it less susceptible to existing treatments. [0009] Despite the advent of vaccines and other treatments, a need remains for novel treatments that target the underlying mechanisms by which SARS-CoV-2 triggers the cytokine storm. These novel treatments must also target portions of COVID-19 that are not specific to the virus, such as fevers, coughs, myalgia, pneumonia, localized inflammation, and severe symptoms including pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation, cytokine storms, and multiorgan failures that are the hallmark of severe COVID-19 leading to death. [0010] The blockade of various particular chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis and from the cytokine storm resulting from COVID-19. However, some of these strategies have failed in clinical trials. A better therapy using a new target is warranted to manage this pathogenesis effectively. SUMMARY OF THE INVENTION [0011] As embodied and broadly described herein, an aspect of the present disclosure relates to a molecule of formula ;

;, or a salt thereof. [0012] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating a musculoskeletal disorder in a subject comprising: identifying that the subject has a musculoskeletal disorder; and providing a therapeutically effective amount of a molecule selected from at least one of: ; ; or salts thereof, wherein the molecule reduces at least one of osteoclast differentiation or inflammation. [0013] In one aspect, the musculoskeletal disorder is selected from at least one of arthritis, rheumatoid arthritis (juvenile and adult), synovitis, osteoarthritis, degenerative joint disease, connective tissue diseases, polymyalgia rheumatica, ankylosing spondylitis, polymyositis, bursitis, fibromyalgia, gout, neuralgia, chronic fatigue syndrome, osteoporosis, and bone damage from cancer metastasis to the bone. In another aspect, the method further comprises adding one or more pharmacologically acceptable excipients, fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver. In another aspect, the molecules are formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration. In another aspect, the molecule is formulated for sustained release, controlled release, delayed release, suppository, catheter, or sublingual administration, or direct injection. In another aspect, the molecule is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days. In another aspect, the molecule is administered at a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day; preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; more preferably 1.5-2.5 mg/day; 1.5 mg/day, 2.0 mg/day or 2.5 mg/day. In another aspect, the molecule is administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day. In another aspect, the molecule is administered by infusion. In another aspect, the molecule is administered by infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion. In another aspect, the molecule is administered using a loading dose and a maintenance dose. In another aspect, the molecule is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions. [0014] As embodied and broadly described herein, an aspect of the present disclosure relates to a pharmaceutical composition comprising: a molecule selected from at least one of:

; ; ; [0015] and one or more pharmaceutical acceptable excipients or salts. In one aspect, the one or more pharmaceutical acceptable excipients or salts are selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug delivery. In another aspect, the molecule(s) is/are formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration. In another aspect, the molecule(s) is/are formulated for sustained release, controlled release, delayed release, suppository, catheter, or sublingual administration, or direct injection. In another aspect, the molecule(s) is/are administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days. In another aspect, the molecule(s) is/are administered at a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day; preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; more preferably 1.5-2.5 mg/day; 1.5 mg/day, 2.0 mg/day or 2.5 mg/day. In another aspect, the molecule(s) is/are administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day. In another aspect, the molecule(s) is/are administered by infusion. In another aspect, the molecule(s) is/are administered by infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion. In another aspect, the molecule(s) is/are administered using a loading dose and a maintenance dose. In another aspect, the molecule(s) is/are formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions. [0016] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of preventing or treating a cytokine storm triggered by a coronavirus 2 (SARS-CoV-2) infection in a subject, the method comprising administering to the subject a therapeutically effective amount of an agonist of Kruppel-like factor 2 (KLF2). In one aspect, the subject has been diagnosed with COVID-19. In another aspect, the KLF2 agonist is a vector that expresses KLF2 or increases the expression of KLF2. In another aspect, the KLF2 agonist is formulated with one or more pharmaceutical acceptable excipients or salts selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver. In another aspect, the KLF2 agonist is formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration. In another aspect, the KLF2 agonist is formulated for sustained release, controlled release, delayed release, suppository, catheter, sublingual administration, or direct injection. In another aspect, the KLF2 agonist is administered once daily, once weekly, twice weekly, once every 14 days, or once monthly. In another aspect, the KLF2 agonist is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days. In another aspect, the KLF2 agonist is administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day. In another aspect, the KLF2 agonist is administered by infusion. In another aspect, the infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion. In another aspect, the KLF2 agonist is administered using a loading dose and a maintenance dose. In another aspect, the KLF2 agonist is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions. In another aspect, the KLF2 agonist reduces morbidity or mortality in the clinical course of COVID-19, reduces symptoms caused by SARS- CoV-2, or reduces the need for ventilator dependency. In another aspect, the KLF2 agonist results in a decrease in one or more symptoms related to acute respiratory distress syndrome (ARDS). In another aspect, the one or more symptoms related to the ARDS is selected from the group consisting of a feeling that one cannot get enough air into the lungs, rapid breathing, low oxygen levels in the blood, and clicking, bubbling, or rattling sounds in the lungs when breathing. In another aspect, the KLF2 agonist is administered in combination with a second therapeutic. In another aspect, the second therapeutic is an antiviral drug, an antimalarial drug, an anti- inflammatory drug, an antibiotic, an acid-reducing medicine, a blood thinner, a muscle relaxant, a pain reliever, a sedative, or a diuretic. [0017] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of treating fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of an agonist of Kruppel-like factor 2 (KLF2). In one aspect, the KLF2 agonist is a vector that expresses KLF2 or increases the expression of KLF2. In another aspect, the KLF2 agonist is formulated with one or more pharmaceutical acceptable excipients or salts selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver. In another aspect, the KLF2 agonist is formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration. In another aspect, the KLF2 agonist is formulated for sustained release, controlled release, delayed release, suppository, catheter, sublingual administration, or direct injection. In another aspect, the KLF2 agonist is administered once daily, once weekly, twice weekly, once every 14 days, or once monthly. In another aspect, the KLF2 agonist is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days. In another aspect, the KLF2 agonist is administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day. In another aspect, the KLF2 agonist is administered by infusion. In another aspect, the infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion. In another aspect, the KLF2 agonist is administered using a loading dose and a maintenance dose. In another aspect, the KLF2 agonist is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions. In another aspect, the fibrosis is lung fibrosis, kidney fibrosis, liver fibrosis, or cardiac fibrosis post- infection with SARS-CoV-2. [0018] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of preventing or treating corneal epithelial dystrophies, wound healing, and injuries with a Kruppel-like factor 2 (KLF2) agonist, the method comprising: obtaining or having obtained one or more corneal epithelial stem cells (CESC); contacting the CESC with an amount of a KLF2 agonist sufficient to differentiate the CESC into corneal epithelial cells to form differentiated corneal epithelial cells; and administering to a subject in need thereof with a therapeutically effective amount of the differentiated corneal epithelial cells. In one aspect, wherein the KLF2 agonist is selected from at least one of:

; ; ; or salts thereof. In another aspect, the KLF2 agonist is provided in an amount sufficient to increase would healing. [0018] As embodied and broadly described herein, an aspect of the present disclosure relates to a method of preventing or treating cytokine storm, fibrosis, or both with a Kruppel-like factor 2 (KLF2) agonist, the method comprising: obtaining or having obtained one or more stem cells; contacting the stem cells with an amount of a KLF2 agonist sufficient to differentiate the stem cells to form KLF2 differentiated stem cells; and administering to a subject in need thereof with a therapeutically effective amount of the differentiated KLF2 differentiated stem cells sufficient to prevent or treat cytokine storm, fibrosis, or both. In one aspect, the KLF2 agonist is selected from at least one of:

; ; ; or salts thereof. In an other aspect, the KLF2 agonist is provided in an amount sufficient to reduce cytokine storm in coronavirus infection. BRIEF DESCRIPTION OF THE DRAWINGS [0019] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which: [0020] FIGS.1A and 1B show that pharmacological KLF2 inducers BT880 (FIG.1A) and BT881 (FIG. 1B) have minimal effect on cell viability. [0021] FIGS. 2A and 2B show that BT881 reduces expression of inflammatory molecules (FIG. 2A) and induces anti-inflammatory molecules (FIG. 2B) in an activated environment. [0022] FIG. 3 shows that BT881 induces KLF2 in myeloid cells (RAW264.7 cells without inflammation 24 hrs). [0023] FIG. 4 shows the effect of KLF2 inducers (BT881 and BT880) on osteoclast differentiation, specifically, BT881 reduces expression of osteoclast differentiation-related markers. [0024] FIGS. 5A and 5B show that BT881 reduces mitochondrial (FIG. 5A) and intracellular (FIG. 5B) ROS during osteoclast (OC) differentiation. [0025] FIGS. 6A and 6B show that BT881 reduces the expression of inflammatory molecules (FIG. 6A) and induces the expression of anti-inflammatory molecules (FIG. 6B) during OC differentiation. [0026] FIGS.7A and 7B show western blotting results for osteoclast differentiation using BT 880 and 881, specifically, OC Markers at 6 Days for BT 880 (FIG.7A) and 881 (FIG.7B). [0027] FIG.8 shows OC Markers at 3 Days for BT 880 and 881. [0028] FIG. 9 shows the viability of myeloid cells after addition of various concentrations of BT1005, BT1006, BT1007 for 24 h and 48 h (n=3). [0029] FIGS.10 shows that KLF2 reduced expression levels of inflammatory, and elevated anti- inflammatory marker molecules in Covid N and S transfected cells. Quantitative real-time PCR analysis is shown graphically for the expression of pro-inflammatory factors such as COX2, HIF1α, IL6, MMP3, MMP9, MMP13, p65, and TNFα in the presence or absence of GGTI298 in K562 cells. The expression of anti-inflammatory factors such as Arg1, IL4R, IL10, and KLF2 are also shown in the presence or absence of GGTI298. Results displayed with mean ± SEM (n = 3). [0030] FIGS. 11A to 11D show the reduced intracellular ROS generation by BT881 (via flow cytometry and immunostaining). FIG.11A shows FACS sorting of cells by FSC-A and SSC-A, FIG.11B shows the percent normalized cells and FTIC-A. FIG.11C is a graph that shows mean fluorescence intensity with DCFDA, COVID pathogenesis induces ROS, and that ROS is reduced by BT881. BT881 is reducing sustained ROS production. FIG.11D shows confocal microscopy of the cells marked as treated for DCFDA, DAPI, and merged, and a graph that shows the mean fluorescence intensity with DCFDA. [0031] FIGS. 12A to 12D show the reduced mitochondrial ROS generation by BT881 (via immunostaining and immunostaining). FIG. 12A shows FACS sorting of cells by FSC-A and SSC-A, FIG.12B shows the percent normalized cells and FTIC-A. FIG.12C is a graph that shows mean fluorescence intensity with MitoSOX. COVID pathogenesis induces ROS, and that ROS is reduced by BT881. BT881 is reducing sustained ROS production. FIG. 12D shows confocal microscopy of the cells marked as treated for MitoSOX, DAPI, and merged, and a graph that shows the mean fluorescence intensity with DCFDA. [0032] FIGS.13A and 13B show that BT881 reduced altered mitochondrial membrane potential (via flow cytometry and immunostaining). FIG.13A. Levels of oxygen consumption rate (OCR), which is an indicator of mitochondrial respiration at basal, maximal respiration, proton leak, ATP production, and spare respiratory capacity is shown graphically after Seahorse flux analysis. FIG. 13B. Levels of extracellular acidification rate (ECAR) are shown graphically after Seahorse flux analysis. Results were shown in mean ± SEM (n = 3). [0033] FIGS. 14A to 14D show the effect of BT881 on reduced mitochondrial function in oxygenated (FIG.14A) and non-oxygenated (FIG. 14B) conditions. FIGS.14C and D show the effect of BT881 that reduced mitochondrial function in oxygenated (FIG. 14C) and non- oxygenated (FIG.14D) conditions. [0034] FIGS. 15A and 15B show that BT881 reduces autophagy and downstream signaling pathway molecules. FIG. 15A. Quantitative real-time PCR analysis for the expression of autophagy marker molecules including ATG7, LC3B and BECN1 in the presence or absence of BT881 were presented graphically. FIG. 15B. Representative images of immunofluorescence staining of autophagy markers in the presence or absence of BT881 and their quantified mean intensity graphs were shown. [0035] FIGS.16A to 16D shows that BT881 reduces fibrosis-related gene and protein expression in TGFβ induced fibrosis in lung fibroblast cells (MRC5). FIG.16A. Quantitative real-time PCR analysis for the expression of fibrosis-associated molecules such as αSMA, COL1A1, COL3A1, and COL8A1 in the presence or absence of BT881 were presented graphically. FIG. 16B. Representative images of immunofluorescence staining of inflammatory markers IL1 ^, TNF ^, and MMP9 in the presence or absence of BT881 and their quantified mean intensity graphs were shown. FIG.16C. Using confocal microscopy, in presence of TGF ^ , ^SMA, and Col8A1, both are increased significantly, however in presence of BT881 these markers are reduced to almost normal level.. FIG.16D is a Western blot that shows that BT881 reduced all lung fibrosis-related protein markers. [0036] FIGS. 17A and 17B show an in silico analyses for the interaction of BT881 with Covid spike and nucleocapsid proteins. FIG. 17A(i). 3D ribbon representation of BT881-Covid S complex. FIG. 17A(ii). 3D zoomed image of BT881-Covid S complex. FIG. 17A(iii). 2D representation of BT881-Covid S complex. FIG. 17A(iv). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of Covid S. FIG.17B(i).3D ribbon representation of BT881-Covid N complex. FIG.17B(ii).3D zoomed image of BT881-Covid N complex. FIG.17B(iii).2D representation of BT881-Covid N complex. FIG.17B(iv). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of Covid N. FIG.17C(i).3D ribbon representation of BT881-TGFβR1 complex. FIG.17C(ii).3D zoomed image of BT881-TGFβR1 complex. FIG.17B(iii).2D representation of BT881-TGFβR1 complex. FIG.17B(iv). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of TGFβR1. [0037] FIG. 18 shows the differentiation of Corneal Endothelial Stem Cells (CESC) to Corneal Endothelial Cells (CEC), in the presence of fibronectin, collagen, and no coating in the presence of BT881. [0038] FIG. 19 shows the differentiation of CESC to CES in the presence and absence of GGTI298 (KLF2 inducer), GGPP (KLF2 inhibitor), the GGTI298 at 10 micromolar, 36 hours. [0039] FIGS.20A and 20B shows that BT881 (FIG.20A) and KLF2 induced with GGTI298 (FIG. 20B) mediated differentiation of CESC to CEC at a concentration of 10 micromolar BT881 in the presence of Type I collagen, collagen at 100 mg, GGTI298 at 3.48 mg.ml concentration. [0040] FIGS. 21A and 21B shows that BT881 (FIG. 21A) and KLF2 (FIG. 21B) induces expression of mature corneal endothelial cell markers along with KLF2 at 3 days. FIG.21B shows that KLF2 induced the expression of mature corneal cell markers and inhibition, and inhibition of KLF2 reduced them. [0041] FIG.22 shows that BT881 induced expression of mature corneal endothelial cell markers at the protein level. [0042] FIG.23 shows that BT881 arrested cell cycle at G12 phase during differentiation. [0043] FIG. 24 shows that human Corneal Endothelial Stem Cells (hCESC) accelerated wound healing in HUVEC human endothelial cells. [0044] FIG. 25 shows that human Corneal Endothelial Stem Cells (hCESC) accelerated wound healing in bovine endothelial cells. [0045] FIG. 26 shows that BT881 increased the level of intracellular ROS (2',7'- dichlorofluorescin diacetate (DCFDA)) in CESC. [0046] FIG.27 shows that BT881 increased the level of mitochondrial ROS (mitoSOX) in CESC. [0047] FIG. 28 shows that BT881 increased the mitochondrial membrane potential (JC-1) in CESC. [0048] FIGS.29A to 29C show a Sea Horse Analysis on CESC to CEC using BT881. FIG.29A shows mitochondrial respiration (oxygen consumption rate) and glycolytic function (extracellular acidification). FIG.29B shows that BT881 increased the mitochondrial respiration (oxygenated) in CESC. FIG. 29C show that BT881 increased the mitochondrial respiration (non-oxygenated) in CESC. [0049] FIGS. 30A to 30D show that BT881 interacts with NF-kappaB (p65) to reduce inflammation. FIG.30A shows a 3D ribbon representation of BT881-NFkappaB (p65) complex. FIG.30B shows a 3D zoomed image of the BT881-NFkappaB (p65) complex. FIG.30C shows a 2D graphical representation of BT881-NFkappaB (p65) complex. FIG.30D shows a graphical representation of bonding pattern and bond distance between BT881 and amino acid residues of NFkappaB (p65). DETAILED DESCRIPTION OF THE INVENTION [0050] While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention. [0051] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims. [0052] The present invention is related to the treatment of musculoskeletal disorders such as arthritis and osteoporosis. The present invention includes agonists to Krüppel-like Factor 2 (KLF2) and the use of the same to treat musculoskeletal diseases such as rheumatoid arthritis and osteoporosis. [0053] Krüppel-like Factor 2 (KLF2) is a protein encoded by the KLF2 gene on chromosome 19. This protein belongs to the Krüppel-like factor family of zinc finger transcription factors, and it was shown to be implicated in a variety of biochemical processes such as lung development, embryonic erythropoiesis, epithelial integrity, T-cell viability, and adipogenesis. KLF2 was first discovered in 1995, and many other KLF proteins have been discovered since. [0054] The main feature of the KLF family is the presence of three highly conserved Cysteine2/Histidine2 zinc fingers of either 21 or 23 amino acid residues in length, located at the C-terminus of the protein. These amino acid sequences each chelate a single zinc ion. The zinc fingers enable all KLF proteins to bind to CACCC gene promoters, so although they may serve completely varied functions (due to lack of homology away from the zinc fingers), they all recognize similar binding domains. [0055] The present inventors recognized that targeting a particular cytokine has not led to the development of effective therapies for Rheumatoid arthritis (RA) and other musculoskeletal diseases. Rather, they recognized that it may be better to target one or more factors that regulate many inflammatory cytokines and the osteoclastogenesis process. As RA is very complex and evidence strongly supports that the monocytes (also called myeloid cells due to the origin lineage) and lymphocytes infiltrate into the joints and interact with local cellular constituents for tissue destruction. Given the important role of myeloid cells in this process, a greater understanding of cellular and molecular mechanisms during the differentiation of osteoclasts (OC) was critically important for the development of an effective therapy. The OC is one of the important regulators of bone homeostasis, and hyper-activation of OC damages cartilage and bones leading to various musculoskeletal pathologies including RA. [0056] The transcriptional regulation of OC differentiation is yet to be defined. The inventors have previously shown that a transcription factor, KLF2, critically regulates myeloid cell activation and function and also showed that KLF2 is involved in autophagy during OC differentiation. Based on these observations, the inventors identified KLF2 as a novel transcriptional regulator of OC differentiation through controlling inflammation and autophagy, and thereby a major modulator of RA. The present inventors developed pharmacological inducers of KLF2 to test their effectiveness for RA therapy. [0057] A pharmacological grade agonist of KLF2 was synthesized to increase specificity, reduce toxicity, and off-target effects with potential preclinical candidates. Using structure-activity relationship (SAR) analysis two KLF2 inducers (BT880 and BT881) were generated and tested. Modified compounds (hit-to-lead) were designed to increase their efficacy and specificity. Next, an integrated and iterative approach was used with homology modeling to identify new pharmacophore groups for the pipeline supporting the drug discovery program. The inventors synthesized the novel pharmacological compounds and tested them in various experiments. Their experimental data shows that the KLF2 agonist compounds reduced osteoclast differentiation and inflammation. [0058] Specifically, the inventors synthesized BT881 and BT880 as potential inducers of KFL2. Both compounds have minimal effect on cell viability. Further mRNA expression testing revealed that BT881 reduces the expression of inflammatory molecules and induces anti-inflammatory molecules in an activated cellular environment. Unlike BT880, BT881 induces KLF2 activity in myeloid cells. Therefore, the inventors focused on BT881 as a KLF2 inducer molecule. BT881 reduced the expression of osteoclast differentiation-related markers in cellular models and lowered mitochondrial and intracellular ROS during osteoclast differentiation, and during osteoclast differentiation, it reduced the expression of inflammatory molecules and induced the expression of anti-inflammatory molecules. In addition, the inventors validated their cellular observation of osteoclast differentiation with western blot markers analysis.

. [0059] As used herein, the term “therapeutically effective amount” refers to an amount of the compound, stereoisomers thereof or pharmaceutically acceptable salts thereof, which are effective in preventing, treating, ameliorating, reducing, or eliminating one or more symptoms of musculoskeletal disorders. Non-limiting examples of musculoskeletal disorders include arthritis, rheumatoid arthritis, and osteoporosis. [0060] As used herein, the term “subject” refers to mammals including humans, and the term “administration” refers to providing a predetermined material to a subject in a suitable dosage form, and via a suitable route of administration or method. Those skilled in the art will recognize that the therapeutically effective dosage and the number of administration(s) of the effective ingredient of the present invention may vary depending on the desired effect. [0061] As used herein, the term “prevention” refers to a delay in the occurrence of a disease, disorder, or condition. If the occurrence of disease, disorder, or condition is delayed for an expected time period the prevention may be considered as complete. [0062] As used herein, the term “treatment” refers to the one that partially or completely reduces, ameliorates, alleviates, inhibits, or delays the occurrence of a certain disease, disorder and/or condition, reduces a severity thereof, or reduces the occurrence of at least one symptom or property thereof. [0063] The novel molecules of the present invention can be used for treating musculoskeletal disorders selected from at least one of arthritis, rheumatoid arthritis (juvenile and adult), synovitis, osteoarthritis, degenerative joint disease, connective tissue diseases, polymyalgia rheumatica, ankylosing spondylitis, polymyositis, bursitis, fibromyalgia, gout, neuralgia, chronic fatigue syndrome, osteoporosis, and bone damage from cancer metastasis to the bone (e.g., breast cancer metastasis and prostate cancer metastasis), which damage bone and cartilage. [0064] A dosage unit for use of the molecule(s) of the present invention, may be a single compound or mixtures thereof with other compounds. The compound may be mixed together, form ionic or even covalent bonds. The molecule(s) of the present invention may be administered in oral, intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. Depending on the particular location or method of delivery, different dosage forms, e.g., tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions may be used to provide the molecule(s) of the present invention to a patient in need of therapy that includes the molecule(s). The molecule(s) may also be administered as any one of known salt forms. [0065] The molecule(s) is/are typically administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) selected based on the intended form of administration and as consistent with conventional pharmaceutical practices. Depending on the best location for administration, the molecule(s) may be formulated to provide, e.g., maximum and/or consistent dosing for the particular form for oral, rectal, topical, intravenous injection or parenteral administration. While the molecule(s) may be administered alone, it will generally be provided in a stable salt form mixed with a pharmaceutically acceptable carrier. The carrier may be solid or liquid, depending on the type and/or location of administration selected. [0066] Techniques and compositions for making useful dosage forms using the present invention are described in one or more of the following references: Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2007; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000, and updates thereto; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference, and the like, relevant portions incorporated herein by reference. [0067] For example, the molecule(s) may be included in a tablet. Tablets may contain, e.g., suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and/or melting agents. For example, oral administration may be in a dosage unit form of a tablet, gelcap, caplet or capsule, the active drug component being combined with a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, mixtures thereof, and the like. Suitable binders for use with the present invention include: starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants for use with the invention may include: sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, mixtures thereof, and the like. Disintegrators may include: starch, methyl cellulose, agar, bentonite, xanthan gum, mixtures thereof, and the like. [0068] The molecule(s) may be administered in the form of liposome delivery systems, e.g., small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles, whether charged or uncharged. Liposomes may include one or more: phospholipids (e.g., cholesterol), stearylamine and/or phosphatidylcholines, mixtures thereof, and the like. [0069] The molecule(s) may also be coupled to one or more soluble, biodegradable, bioacceptable polymers as drug carriers or as a prodrug. Such polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta- midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, mixtures thereof, and the like. Furthermore, the molecule(s) may be coupled one or more biodegradable polymers to achieve controlled release of the molecule(s), biodegradable polymers for use with the present invention include: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels, mixtures thereof, and the like. [0070] In one embodiment, gelatin capsules (gelcaps) may include the molecule(s) and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Like diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as immediate-release, mixed-release or sustained-release formulations to provide for a range of release of medication over a period of minutes to hours. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere. An enteric coating may be used to provide selective disintegration in, e.g., the gastrointestinal tract. [0071] For oral administration in a liquid dosage form, the oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents, mixtures thereof, and the like. [0072] Liquid dosage forms for oral administration may also include coloring and flavoring agents that increase patient acceptance and therefore compliance with a dosing regimen. In general, water, a suitable oil, saline, aqueous dextrose (e.g., glucose, lactose and related sugar solutions) and glycols (e.g., propylene glycol or polyethylene glycols) may be used as suitable carriers for parenteral solutions. Solutions for parenteral administration include generally, a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering salts. Antioxidizing agents such as sodium bisulfite, sodium sulfite and/or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA may also be included to increase stability. In addition, parenteral solutions may include pharmaceutically acceptable preservatives, e.g., benzalkonium chloride, methyl- or propyl- paraben, and/or chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field, relevant portions incorporated herein by reference. [0073] For direct delivery to the nasal passages, sinuses, mouth, throat, esophagus, trachea, lungs and alveoli, the molecule(s) may also be delivered as an intranasal form via use of a suitable intranasal vehicle. For dermal and transdermal delivery, the molecule(s) may be delivered using lotions, creams, oils, elixirs, serums, transdermal skin patches and the like, as are well known to those of ordinary skill in that art. Parenteral and intravenous forms may also include pharmaceutically acceptable salts and/or minerals and other materials to make them compatible with the type of injection or delivery system chosen, e.g., a buffered, isotonic solution. Examples of useful pharmaceutical dosage forms for administration of molecule(s) may include the following forms. [0074] Capsules. Capsules may be prepared by filling standard two-piece hard gelatin capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose and 6 milligrams magnesium stearate. [0075] Soft Gelatin Capsules. A mixture of active ingredient is dissolved in a digestible oil such as soybean oil, cottonseed oil or olive oil. The active ingredient is prepared and injected by using a positive displacement pump into gelatin to form soft gelatin capsules containing, e.g., 100-500 milligrams of the active ingredient. The capsules are washed and dried. [0076] Tablets. A large number of tablets are prepared by conventional procedures so that the dosage unit was 100-500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. [0077] To provide an effervescent tablet appropriate amounts of, e.g., monosodium citrate and sodium bicarbonate, are blended together and then roller compacted, in the absence of water, to form flakes that are then crushed to give granulates. The granulates are then combined with the active ingredient, drug and/or salt thereof, conventional beading or filling agents and, optionally, sweeteners, flavors and lubricants. [0078] Injectable solution. A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in deionized water and mixed with, e.g., up to 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized using, e.g., ultrafiltration. [0079] Suspension. An aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin. [0080] For mini-tablets, the active ingredient is compressed into a hardness in the range 6 to 12 Kp. The hardness of the final tablets is influenced by the linear roller compaction strength used in preparing the granulates, which are influenced by the particle size of, e.g., the monosodium hydrogen carbonate and sodium hydrogen carbonate. For smaller particle sizes, a linear roller compaction strength of about 15 to 20 KN/cm may be used. [0081] Kits. The present invention also includes pharmaceutical kits useful, for example, for the treatment of cancer, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount(s) of the molecule(s). Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized. [0082] Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols, or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorings and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. [0083] As used herein, the term “chewable” refers to a semi-soft, palatable, and stable chewable treat without the addition of water. It should be appreciated to the skilled artisan that a chewable composition will be stable and palatable, fast disintegrating, semi-soft medicated chewable tablets (treats) by extrusion without the addition of extraneous water. A soft chewable tablet does not harden on storage and is resistant to microbial contamination. A semi-soft chewable contains a blend of any one or more binders, flavors, palatability enhancers, humectants, disintegrating agents, non-aqueous solvents, and diluents that are plasticized with liquid plasticizers, such as glycols and polyols to make them ductile and extrudable. The chewable can be made by extrusion, e.g., including fats or lipids as plasticizers and binding agents, is manufactured in the absence of added water, uses plasticizers to replace water in extrudable matrices, contains humectants to maintain the extrudable chew in a pliant and soft state during its shelf life, or any combination thereof. The chewable form may be provided in conjunction with one or more flavorants and/or taste masking agents that improve the taste of the formulation greater than 10, 20, 30, 40, 50, 60, 70, 80, or 90%. The chewable can include the active agent and the ion exchange resin to enhance taste masking. [0084] For topical administration, the composition can be incorporated into creams, ointments, gels, transdermal patches, and the like. The composition can also be incorporated into medical dressings, for example, wound dressings, e.g., woven (e.g., fabric) dressings, or non-woven dressings (e.g., gels or dressings with a gel component). The use of alginate polymers in dressings is known, and such dressings, or indeed any dressings, may further incorporate the alginate oligomers of the invention. [0085] Example 1. KLF2 agonist effects on inflammation and differentiation. [0086] By evaluating the effect of a pharmacological compound BT881 (KLF2 inducer) on myeloid cells during inflammation and differentiation the inventors found that BT881 significantly reduces osteoclast differentiation and inflammation, which can be used for the therapy of musculoskeletal diseases like arthritis and osteoporosis. [0087] MTT assay for cell proliferation. The RAW264.7 cells (1 x 10⁴/ well) were cultured in DMEM media in 96-well plates, and after overnight culture, various concentration of either BT880 and BT881 molecules were added using 5-100 ^M concentrations. Cells were incubated at 37 ^C as per requirement of the experiment. MTT solution was added per well making final concentration of 0.45 mg/mL (MTT added plates and solutions were kept and in dark). Cells were incubated for 4 h at 37 ^C in the dark.100 mL of solubilizing solution (containing 1g of SDS in 10 mL of 0.01 M HCl) was added to each well to dissolve formazan crystals and mixed properly by shaking. Absorbance was measured at 570 nm using a beta plate reader. [0088] RNA extraction and real-time PCR. The myeloid (RAW264.7) cells were grown on six- well plates at the density of 1 x 10⁵/ well in DMEM media. After overnight incubation, BT880 and BT881 molecules (10 ^M) were added in the cells for induction of KLF2, and again incubated for 36 h in CO₂ incubator at 37° C. Afterward, TRIzol reagent was used to extract total RNA according to the manufacturer's instructions. cDNA from 1 µg of RNA was synthesized using a high-capacity RNA-to-cDNA Kit following manufacturer’s protocol. Real-time PCR amplification for the inflammatory and anti-inflammatory molecules, and osteoclast differentiation-related marker molecules was performed with SYBR Green PCR Kit. Ct values (threshold cycle values) were calculated and normalized using β-actin levels to estimate the relative expression of each target gene. Analyses were conducted in triplicates for each sample. Primers were purchased from Incorporated DNA Technologies (IDT), IA, USA. [0089] Osteoclastic differentiation. Osteoclastic differentiation was determined by TRAP staining according to the manufacturer’s protocol. Briefly, RAW264.7 cells (1x10⁴ cells/well), were cultured on a coverslip in a 6-well plate for differentiation to osteoclasts using OC differentiation media in the presence or absence of BT880/BT881. On the 6th day of differentiation, coverslips were washed with 1 x PBS and fixed with 4% PFA for 20 min at room temperature, and then, staining was performed. [0090] Evaluation of reactive oxygen species. To determine the intracellular ROS, DCFDA staining was performed on live myeloid (RAW264.7) cells. The cells were grown on six-well plates, one set with coverslips and the other set without coverslips, at the density of 1 x 10⁵/well in DMEM media with or without BT880 and BT881 molecules (10 ^M) for 24 h. The cells of six- well plates without coverslips were stained with 20 µM of DCFDA solution in PBS for 30 min at 37° C, suspended in fresh medium, and analyzed immediately with a FACSVerse flow cytometer using FACSuite software (BD Biosciences, NJ, USA). On the other hand, for microscopic analysis, the cells grown on coverslips with or without BT880 and BT881 molecules (10 ^M) were washed with HBSS media and incubated with 5 µM of DCFDA solution for 30 min at 37 °C. DAPI was used to mount the coverslips on the glass slide after they had been thoroughly washed with PBS three times at intervals of 5 min. An ultra-high-resolution confocal microscope was used to take fluorescence images (Leica Stellaris 8 STED, Germany) and LAS X image analysis software was used to analyze the images. The experiments were conducted in three different sets. Several images of different areas of the coverslip were captured for quantification. [0091] Evaluation of mitochondrial superoxide. Mitochondrial superoxide production was detected using MitoSOX red staining and flow cytometry. Briefly, the cells were grown on six- well plates, one set with coverslips and the other set without coverslips, at the density of 1 x 10⁵/well in DMEM media with or without BT880 and BT881 molecules (10 ^M) for 24 h on coverslips for microscopy and without coverslips for flow cytometry in DMEM medium for 36 h. After incubation, the coverslips containing cells were washed with ice-cold PBS carefully and then incubated for 30 min at 37 °C with 2.5 µM of mitoSOX red. DAPI was used to mount the coverslips on the glass slide after incubation and washing with PBS three times. Fluorescence images were captured using a super-resolution confocal microscope (Leica Stellaris 8 STED, Germany), and LAS X image analysis software was used to analyze the images. Three different sets of experiments were conducted, and five images were taken from different areas of the coverslip for quantification. Similar to microscopy, the cells grown without coverslips were stained with mitoSOX red, and immediately analyzed with flow cytometry using a FACSVerse flow cytometer and FACSuite software (BD Biosciences, NJ, USA). [0092] Protein isolation and western blot analysis. The myeloid (RAW264.7) cells were lysed with ice-cold RIPA buffer and subjected to western blotting (WB) after growing them in a 6-well plate for the culture for 24h after the addition of with or without BT880 and BT881 molecules (10 ^M). After washing the cells three times with ice-cold PBS, they were lysed on ice using RIPA buffer. Pellets were then removed by centrifugation. Protein concentrations were measured using a BCA protein assay kit. A total of 40 ^g of proteins was electrophoresed on SDS-PAGE gels and transferred to PVDF membranes. A 5% nonfat milk was applied to the membranes for blocking for 1 h at room temperature prior to incubation with primary antibodies overnight at 4 °C. Membranes were washed and then incubated with the appropriate HRP-conjugated secondary antibodies for two hours at room temperature. The bands of protein were visualized using an ECL- developing method. A densitometric analysis of three separate experimental sets was conducted using the Fiji Image J software. [0093] FIGS.1A and 1B show that pharmacological KLF2 inducers BT880 (FIG.1A) and BT881 (FIG.1B) have minimal effect on cell viability. [0094] FIGS.2A and 2B show that BT881 reduces expression of inflammatory molecules (FIG. 2A) and induces anti-inflammatory molecules (FIG.2B) in an activated environment. [0095] FIG. 3 shows that BT881 induces KLF2 in myeloid cells (RAW264.7 cells without inflammation 24 hrs). [0096] FIG. 4 shows the effect of KLF2 inducer (BT881) on osteoclast differentiation, specifically, BT881 reduces expression of osteoclast differentiation-related markers. [0097] FIGS. 5A and 5B show that BT881 reduces mitochondrial (FIG. 5A) and intracellular (FIG.5B) ROS during osteoclast (OC) differentiation. [0098] FIGS. 6A and 6B show that BT881 reduces the expression of inflammatory molecules (FIG. 6A) and induces the expression of anti-inflammatory molecules (FIG. 6B) during OC differentiation. [0099] FIGS.7A and 7B show western blotting results for osteoclast differentiation using BT 880 and 881, specifically, OC Markers at 6 Days for BT 880 (FIG. 7A) and 881 (FIG. 7B). [0100] FIG. 8 shows OC Markers at 3 Days for BT 880 and 881. [0101] Small scale preclinical studies showed minimal toxicity in mice with KLF2 inducer, BT881- Small-scale toxicity, pharmacokinetics, and pharmacodynamics studies were performed for BT881 using 3 mice that showed no toxicity up to 50 mg/Kg BW (oral) and 2.5 mg/kg BW (IP); and were safe for maximum tolerance dose, and T1/2 parameters were undetectable. Parameters evaluated are Cmax: maximum blood concentration; t^max: time of maximum blood concentration; t^1/2: half-life, data points used for half-life determination are in bold; MRT last: mean residence time, calculated to the last observable time point; AUC last: area under the curve, calculated to the last observable time point; AUC∞: area under the curve, extrapolated to infinity; BLOQ: below the limit of quantitation (0.300 ng/mL); NA: not applicable; ND: not determined. Dose-normalized by dividing the parameter by the measured dose in mg/kg. ND: not determined because the r² for elimination part is either <0.85 or not enough data points (Table. 1). These results clearly show that BT881 and this class of this compounds improve the PK/PD profile.

[0102] Synthesized BT881 analogs showing minor effect on cell viability. The inventors synthesized additional pharmacological grade, boron-based compounds, which increased specificity, reduced toxicity and off-target effect as further KLF2 agonists. BT1005, BT1006, and BT1007 were synthesized using structure-activity relationship (SAR) study approaches. The chemical structures of BT1005, BT1006, and BT1007 are [0103] Their molecular weights are 422.68, 402.61, and 340.53 Dalton respectively. Cell viability assay revealed that BT1005, BT1006, and BT1007 did not show any deleterious effect on cell viability up to 50 ^M, 10 ^M, and 100 ^M respectively (FIG. 9). [0104] FIG. 9 shows the viability of myeloid cells after addition of various concentrations of BT1005, BT1006, BT1007 for 24 h and 48 h (n=3). [0105] Example 2. KLF2 agonist effects in Covid model. [0106] Induction of KLF2 resulted in lowering the elevated expression of inflammatory markers induced by in vitro Covid model. [0107] The present inventors found that the induction of KLF2 resulted in lowering the elevated expression of inflammatory markers induced by an in vitro Covid model. Induction of Covid also raised the level of oxidative stress, and autophagy, and resulted in mitochondrial dysfunctions and upregulation of KLF2 reduced the elevated levels of oxidative stress, and autophagy markers, and restored mitochondrial functions. Furthermore, the induction of KLF2 minimized the expression of fibrosis-associated markers in an induced lung fibrosis model to mimic post-Covid syndrome. Finally, an in silico analysis revealed that the GGTI298 (chemical inducer of KLF2) displayed a strong interaction with both Covid nucleocapsid protein and spike glycoprotein, validating the effect of KLF2 in nullifying the Covid-associated pathogenesis and post-Covid syndrome. [0108] Reagents and antibodies. K562 (#TIB-71), and MRC5 (#CCL-171) cell lines were collected from the American Type Culture Collection (ATCC). The inventors procured GGTI-298 (#16176) from Cayman Chemical, BCA protein assay kit (#23225), propidium iodide (# p3566), JC-1 dye (#T3168), and mitoSOX red compound (#M36008) from Thermo Fischer Scientific, MA, USA, 4% paraformaldehyde (PFA, #sc-281692) from Santa Cruz Biotechnology, TX, USA, Triton X-100 (#T8787), Dulbecco's modified Eagle medium (DMEM, #11995065), RIPA lysis buffer (#20-188), and 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA, #4091-99-0) from Sigma-Aldrich, MO, USA, TRIzol reagent (#15596026) and 4,6-diamidino-2-phenylindole dihydrochloride (DAPI, #D1306), Alexa Fluor 488 (#A11001) and Alexa Fluor 647 (#A21235) from Invitrogen Corporation, MA, USA, and PVDF membrane (#1620115) from Bio-Rad Incorporation, CA, USA. The Primary antibodies, Beclin1 (#4122 S), ATG7(# 8558 S), AKT (#4691 S), COLA1 (#72026), COL3A1(#98908), Cov S (#42172S), Cov N (33717S), GAPDH (#2118 S), c-Jun (9165S), HRP (horseradish peroxidase)-labeled secondary antibodies (#7074, and #7076), LC3B (#12741 S), and phospho p38MAPK (#4511 S), and p38MAPK (#9212 S) were obtained from Cell Signaling Technology, MA, USA, and ATG5 (#ab12994), and COL8A1 (#ab58776) were purchased from Abcam Inc, Cambridge, UK. The enhanced chemiluminescence kit (RPN2232) from Amersham Pharmacia Biotechnology, Amersham, UK, the high-capacity RNA-to-cDNA kit (#4387406), and the SYBR Green PCR Kit (#4309155) were all obtained from Applied Biosystems, MA, USA. The RPMI-1640 medium (#11875093), penicillin-streptomycin (#15140122), Puromycin (#A1113803), Hank’s balanced salt solution (HBSS, #14170161), and phosphate buffered saline (PBS, #10010023) was obtained from Thermo Fisher, USA. The Eagle's Minimum Essential Medium (# 670086) from Fisher Scientific, USA, TGF-β from Biolegend, CA, USA (Cat # 763104), and fetal bovine serum (FBS, #S11550) from Bio-Techne, MN, USA. [0109] Transfection of K562 cells with Covid N and Covid S expression vectors. The inventors transfected plasmids of Covid spikes and nucleocapsid proteins from SARS-CoV-2 (Covid) into K562 cells to create an in vitro model of Covid infection following an earlier established protocol (31). In brief, a 1.5 mL tube was filled with 32 µL of SARS-CoV-2 (Covid) S HexaPro plasmid DNA (0.069 µg/mL) mixed with 1.7 µL of pLVX-SARS-Cov-2 (Covid) N (0.16 µg/µL) and 3.8 µL of 3M sodium acetate (NaAc) pH 5.2, and finally added 100 µL of 100% cold ethanol. Following storage in the -20 °C for 30 min, the DNA samples were centrifuged at 15000 rpm in a tabletop microcentrifuge, washed once with 0.5 mL of 100% ethanol, and allowed to air dry. The plasmid DNAs were resuspended in 10 µL of sterile water to perform the transfection process. The transformation and amplification of plasmid DNA was performed in DH5 ^ Escherichia coli cells following the protocols of the competent cells and plasmid purification kit, respectively. [0110] K562 cells were seeded at a density of 2 x 10⁵ cells per mL in RPMI 1640, containing10% FBS in a 6-well plate. The 90 µL of EMEM was added with 10 µL of Covid S, Covid N, and 6 µL of FuGene HD, and mixed well. The mixture was incubated at room temperature for 10 min and added to each well of the 6-well plate containing K562 Cells. The plate was then incubated in CO2 incubator for 5 h followed by 3 mL of RPMI 1640 was added, and kept in CO2 incubator for overnight. After that, the transfected cells were transferred to a 100 mM plate in 10 mL of RPMI 1640 and allowed the cells to grow for 24 h. Once the cells were transfected, the inventors mixed them with 20 mL of growth medium in a 50 mL tube. The cells were aliquoted into a 24-well plate at a volume of 1 mL per well after being treated with puromycin at a final concentration of 2 µg/mL. Approximately two to four weeks were required for the cells to be selected. The selected transfected K562 cells were cultured in 100 mM plates in 10 mL of RPMI 1640 containing puromycin (2 µg/mL). [0111] RNA extraction and real-time PCR. The Covid N and S transfected and mock transfected K562 cells were grown on six-well plates at the density of 1 x 10⁴/ well in RPMI media. After overnight incubation, the GGTI298 was added in Covid N and S transfected K562 cells for induction of KLF2, and again incubated for 36 h in CO₂ incubator at 37° C. Afterward, TRIzol reagent was used to extract total RNA according to the manufacturer's instructions. The inventors have synthesized cDNA from 1 µg of RNA using a high-capacity RNA-to-cDNA Kit following manufacturer’s protocol. Real-time PCR amplification was performed with SYBR Green PCR Kit. Ct values (threshold cycle values) were calculated and normalized using β-actin levels to estimate the relative expression of each target gene. Analyses were conducted in triplicates for each sample. Primers were purchased from Incorporated DNA Technologies (IDT), IA, USA. [0112] Evaluation of reactive oxygen species. To determine the intracellular ROS, DCFDA staining was performed on live K562 cells. The Covid N and S transfected and mock transfected K562 cells were grown on six-well plates, one set with coverslips and the other set without coverslips, at the density of 1 x 10⁵/well in RPMI media with or without GGTI298 for 24 h. The cells of six-well plates without coverslips were stained with 20 µM of DCFDA solution in PBS for 30 min at 37° C, suspended in fresh medium, and analyzed immediately with a FACSVerse flow cytometer using FACSuite software (BD Biosciences, NJ, USA). On the other hand, for microscopic analysis, the cells grown on coverslips with or without GGTI-298 were washed with HBSS media and incubated with 5 µM of DCFDA solution for 30 min at 37 °C. DAPI was used to mount the coverslips on the glass slide after they had been thoroughly washed with PBS three times at intervals of 5 min. An ultra-high-resolution confocal microscope was used to take fluorescence images (Leica Stellaris 8 STED, Germany) and LAS X image analysis software was used to analyze the images. The experiments were conducted in three different sets. Several images of different areas of the coverslip were captured for quantification. [0113] Evaluation of mitochondrial superoxide. Mitochondrial superoxide production was detected using MitoSOX red staining and flow cytometry. Briefly, K562 cells (1×10⁴ cells/well) were cultured in six-well plates in three separate groups: Mock transfected cells (Control), Covid (N + S) transfected cells with or without GGTI298 on coverslips for microscopy and without coverslips for flow cytometry in RPMI medium for 36 h. After incubation, the coverslips containing cells were washed with ice-cold PBS carefully and then incubated for 30 min at 37 °C with 2.5 µM of mitoSOX red. DAPI was used to mount the coverslips on the glass slide after incubation and washing with PBS three times. Fluorescence images were captured using a super- resolution confocal microscope (Leica Stellaris 8 STED, Germany), and LAS X image analysis software was used to analyze the images. Three different sets of experiments were conducted and five images were taken from different areas of the coverslip for quantification. Similar to microscopy, the cells grown without coverslips were stained with mitoSOX red, and immediately analyzed with flow cytometry using a FACSVerse flow cytometer and FACSuite software (BD Biosciences, NJ, USA). [0114] Evaluation of mitochondrial membrane potential. The membrane potential of mitochondria was evaluated using JC1 (5,5′,6,6′-tetrachloro-1,1′,3,3′- tetraethylbenzimidazolylcarbocyanine iodide) dye. A red fluorescent signal is produced by mitochondrial JC1 as a result of its ability to enter and polymerize to form J-aggregates. JC1 emits green fluorescence when it is present as a J-monomer in the cytoplasm. Experiment was set up for both microscopic analysis and flow cytometry analysis, as described above. The cells were probed with 10 µM of JC1 dye for 20 min at 37° C after washing with PBS. After staining, the cells were washed with PBS three times and analyzed with a FACSVerse flow cytometer and super- resolution confocal microscope (Leica Stellaris 8 STED, Germany). [0115] Seahorse flux analysis for mitochondrial respiration and glycolysis evaluation. The inventors assessed mitochondrial function of transfected cells with and without GGTI298 using an Agilent XFe24 flux analyzer for MitoStress and glycolytic properties. In brief, K562 cells were cultured on a seahorse cell culture plate in RPMI media with or without GGTI298. Assay media was prepared on the day of the assay using Seahorse XF DMEM (Agilent, USA) with pyruvate, glutamine, and glucose supplements. The RPMI media was removed and rinsed once with assay media in each well. Two washes with assay media were performed for each well and 500 µL assay media was added in the final step. Before the assay, cells were incubated at 37° C for one hour in a non-CO2 incubator. Following the assay, the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured using the standard protocol, and the experimental data were analyzed using Agilent's Seahorse software 2.6.1. A total of four independent inductions were carried out at each time point. The ATP synthase inhibitor, oligomycin (1.5 µM), the uncoupler carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP, 1 µM), the complex III inhibitor rotenone, and antimycin A (2 µM) was added to the wells for determining the properties of oxidative phosphorylation. The cell culture was also treated with D-glucose (10 mM), oligomycin (1 µM), and 2-deoxy-D-glucose (2-DG, 50 mM) as part of the glycolysis evaluation. The same software was used to evaluate and calculate OCR and ECAR. [0116] Cell cycle analysis. The cell cycle analysis was performed by a FACS Calibur flow cytometer (BD Biosciences, NJ, USA) after staining with PI as described earlier (32). Following treatment, the cells were collected after 24 and 48 h and fixed with 70% ethanol at 4° C to determine the distribution of the cell population in different phases of the cell cycle. The cell pellet was then suspended in PBS after centrifugation at 2500 rpm for 5 min at 4° C and treated with RNase A (10 μg/mL) (Sigma, USA) and resuspended in PBS, and kept for 15 min at room temperature. Finally, the cells were incubated in the dark with 10 μg/mL of PI (Sigma, USA) for 15 min at room temperature. After washing with PBS cells were subjected to analysis using 10,000 events per sample. [0117] Induction of KLF2 in a model of fibrogenesis. [0118] Development of in-vitro fibrogenesis. To develop fibrogenesis the inventors adapted an in vitro method, which was established earlier (33). In brief, MRC5 cells were isolated from the culture, and resuspended in DMEM medium and plated in 6-well plates at the density of 1×10⁴. After overnight incubation in CO₂ incubator, the cells were stimulated with TGF-β (1 μg/mL), at the same time, GGTI298 was added in one well of six-well plate and cultured for 5 days in the same medium. The medium was replaced with fresh DMEM medium containing TGF-β with and without GGTI298 and GGTI298 every second day. The medium of control group cells had neither TGF-β nor GGTI298. On the day 6 after fibrosis induction, the cells were harvested for RT-PCR, western blot and ICC analysis. [0119] Protein isolation and western blot analysis. Cells were lysed with ice-cold RIPA buffer and subjected to western blotting (WB) after growing them in a 6-well plate for the desired period and under the desired conditions. After washing the cells three times with ice-cold PBS, they were lysed on ice. Pellets were then removed by centrifugation. Protein concentrations were measured using a BCA protein assay kit. A total of 40 ^g of proteins was electrophoresed on SDS-PAGE gels and transferred to PVDF membranes. A 5% nonfat milk was applied to the membranes for blocking for 1 h at room temperature prior to incubation with primary antibodies overnight at 4°C. Membranes were washed and then incubated with the appropriate HRP-conjugated secondary antibodies for two hours at room temperature. The bands of protein were visualized using an ECL- developing method. A densitometric analysis of three separate experimental sets was conducted using the Fiji Image J software. [0120] Immunofluorescence staining. To visualize the expressions of the autophagy, mitophagy and signaling pathways-related molecules in transfected K562, and fibrosis-related markers in MRC5 cells, the experiment were designed for both cells as described above and immunofluorescence (IF) staining. In short, after termination of experiment setup, the cells were fixed with 4% PFA for 30 min. After washing with 1× PBS, cells were permeabilized with 0.1% Triton X-100 for 15 min at room temperature and blocked with 1% BSA for 30 min. Then, cells were incubated with 200 μL of primary antibody overnight at 4° C. The next day, cells were washed with 1× PBS followed by incubated with 200 μL of secondary anti-rabbit or anti-mouse antibodies for 45 min in the dark. After incubation, cells were washed thrice with 1× PBS and mounted using DAPI on glass slides. Fluorescence images were captured using a super-resolution confocal microscope (Leica Stellaris 8 STED, Germany), using a 100x objective, and images were analyzed using LAS X image analysis software. Three separate sets of experiments were performed. Five images were taken from different areas of the coverslip for quantification. [0121] Differential gene expression analysis. For computational differential gene expression analysis, the inventors have selected data sets of the blood leukocyte cells from GSE157103 data bank for the expression analysis of the genes of interest for the Covid-19 infected blood samples as the K562 cells belong to a progenitor lineage of blood leukocyte cells (34, 35). The inventors downloaded the raw data files from the Gene Expression Omnibus (GEO) database and were normalized by using AltAnalyzer software keeping the default setting field for the analysis (36). The AltAnalyzer software was downloaded from the Cincinnati Children’s website. The fold changes ≥2 has considered upregulated and ≤2-fold considered as downregulated. The normalized gene expression data has been used to generate a differential expression complex heat map for the patients keeping healthy individuals as a control using the Omics Playground server (37). The volcano plot program of the Galaxy web server has been applied to get the overall differential expression pattern. To understand the KLF2 correlated gene sets for each data set, the inventors have applied the trend. limma, deseq2, and edgeR statistical programs on the Omics Playground webserver. Then, the inventors generated a correlation network by the Fruchterman-Reingold layout, a force-directed layout algorithm on the same platform (36). The correlation value ≤0.4 was considered a significantly correlated gene with KLF2. Finally, the dot plot was created on the Morpheus web server to get the overall expression pattern of genes of interest in leukocyte data sets (37). [0122] Molecular docking. Structure optimization of GGTI298 was performed using Gaussian 09 software at semi-empirical PM6 level of theory and gas phase for the ligand and protein optimization using in-silico molecular docking study (38). The crystal structure of the SARS- CoV-2 nucleocapsid dimerization domain and spike glycoprotein were obtained from the protein data bank (RSCB PDB ID: 6WZO and 7DDN respectively). The whole sequence was considered for further study and the water atoms were isolated using the PyMOL Molecular Graphics System (version 1.1) software package (39). Afterward, the Swiss-PDB viewer software suit (version 4.1.0) was used to check and optimize the protein structure to get the structure of minimum energy. Finally, the ligand-protein's nonbonding interactions and binding affinities were calculated using the Autodock Vina software package. Next, this molecular interaction with the respective protein was analyzed using PyMOL Molecular Graphics System (version 1.1) and Discovery Studio 4.1 (39). [0123] Statistical analysis. Each experiment was performed in triplicate, and the results were reported as mean ± SD (SEM). A statistical analysis was performed using Graph Pad Prism 9.0 for Windows (Graph Pad Software, San Diego, CA, USA). Tukey's multiple comparisons test was conducted using a one-way analysis of variance (ANOVA). Student's t-tests with two-tailed unpaired samples were used for comparing data between two groups. A p-value of less than 0.05 was considered significant. [0124] Effect of KLF2 on inflammatory and anti-inflammatory molecules during induction of COVID. [0125] To mimic the human pathogenesis, the inventors constructed the plasmids of Covid nuclear (N) and spike (S) protein and transfected in lymphoid cells (K562) using FuGENE transfection method, followed by puromycin selection, and confirmed the expression of both Covid S and N proteins by western blot (WB) methods. Quantitative RT-PCR analysis showed that the expression of pro-inflammatory factors such as COX2, HIF1α, IL6, MMP3, MMP9, MMP13, p65, and TNFα were significantly increased in Covid transfected cells compared to the mock (empty vector) transfected cells (FIG. 10). However, when the inventors added KLF2 inducer (GGTI298) to the transfected cells for 24 h the expressions of those pro-inflammatory factors were significantly decreased almost to the baseline (FIG. 10). On the other hand, expression of anti- inflammatory factors such as IL4R and IL10 were significantly decreased after the induction of Covid. However, after the addition of KLF2 inducer (GGTI298) to the transfected cells for 24 h, the expressions of those anti-inflammatory factors (including Arg1) were significantly increased. In addition, the KLF2 level was significantly decreased in Covid transfected cells, however, after addition of KLF2 inducer (GGTI298) to the transfected cells for 24 h, the expression of KLF2 was increased significantly, over more than 4-fold. These results indicate that the KLF2 inducer has the power to reduce the inflammatory cytokines and induce the pro-inflammatory factors made after the induction of Covid. [0126] Differential gene expression analysis during human Covid pathogenesis. [0127] To confirm the in vitro data, the inventors analyzed the leukocyte samples of Covid- infected patients and healthy individuals using the GEOdata base # GSE157103. Analyzed results showed that the proinflammatory genes, COX2, HIF1α, IL6, MMP3, MMP9, MMP13, and p65 (RELA) were highly expressed in Covid-infected patients compared to the controls (healthy individuals), whereas, the expression of anti-inflammatory molecules, Arg1 and IL4R along with KLF2 were reduced in Covid-infected patients. These data strongly support the in vitro experimental model results. The inventors also observed that the expression of autophagy molecules such as ATG5, ATG7, Beclin1, and LC3B was increased during Covid pathogenesis, and their upstream signaling pathway molecules, cJun, Fos, Stat3, Map-kinase (MAPK) were also activated. Further, the inventors found that the cell cycle related molecules such as H2AX and ATR were increased and checkpoint proteins, CHK1 and CHK2 were decreased in Covid patients. String data analysis demonstrated that the KLF2 is strongly connected with most of the molecules, related to inflammation, autophagy, and cell cycle along with their upstream molecules those are involved in human Covid pathogenesis. [0128] FIGS. 11A to 11D show the reduced intracellular ROS generation by BT881 (via flow cytometry and immunostaining). FIG.11A shows FACS sorting of cells by FSC-A and SSC-A, FIG.11B shows the percent normalized cells and FTIC-A. FIG.11C is a graph that shows mean fluorescence intensity with DCFDA, COVID pathogenesis induces ROS, and that ROS is reduced by BT881. BT881 is reducing sustained ROS production. FIG.11D shows confocal microscopy of the cells marked as treated for DCFDA, DAPI, and merged, and a graph that shows the mean fluorescence intensity with DCFDA. [0129] Effect of BT881 on reactive oxygen species (ROS) generation and mitochondrial membrane potential. [0130] To examine the effect of KLF2 on the intracellular ROS generation, the inventors have performed the DCFDA staining of the Covid N and S transfected K562 cells and after addition of GGTI298 for 24 h, which were analyzed by flowcytometry. The obtained results showed that Covid N and S transfected K562 cells exhibited the generation of significantly higher amount of ROS compared to the vehicle transfected control cells. However, after addition of GGTI298, the amount of ROS was decreased significantly (FIG.12A, Upper panels). The DCFDA staining was further verified under super resolution confocal microscopy, and found that the Covid N and S transfected K562 cells exhibited the significantly higher amount of ROS generation compared to the empty vector transfected control cells. However, after addition of GGTI298, the amount of ROS was decreased significantly (FIG.12A, Lower panels). [0131] FIGS. 12A to 12D show the reduced mitochondrial ROS generation by BT881 (via immunostaining and immunostaining). FIG. 12A shows FACS sorting of cells by FSC-A and SSC-A, FIG.12B shows the percent normalized cells and FTIC-A. FIG.12C is a graph that shows mean fluorescence intensity with MitoSOX. COVID pathogenesis induces ROS, and that ROS is reduced by BT881. BT881 is reducing sustained ROS production. FIG. 12D shows confocal microscopy of the cells marked as treated for MitoSOX, DAPI, and merged, and a graph that shows the mean fluorescence intensity with DCFDA. [0132] To determine the effect of KLF2 on the mitochondrial ROS generation, the inventors have performed the MitoSOX staining of the Covid N and S transfected K562 cells, and after addition of BT881 for 24 h, which were analyzed by flowcytometry. The inventors found that the generation of mitochondrial ROS was significantly higher in Covid N and S transfected K562 cells compared to the empty vector transfected control cells. However, when the inventors added BT881 to the Covid N and S transfected cells, the amount of mitochondrial ROS was decreased significantly (FIG. 12A- 12C). The MitoSOX staining was further evaluated under super resolution confocal microscopy and the results were similar to the flowcytometry (FIG.12D). [0133] Next, the inventors examined the mitochondrial membrane potential (MMP) of the Covid N and S transfected K562 cells and after addition of BT881 for 24 h using JC-1 staining and analyzed by flowcytometry. The inventors found that the Covid N and S transfected K562 cells exhibited the remarkable loss of MMP compared to the empty vector transfected control cells. However, the addition of BT881 to transfected cells significantly reversed the loss of MMP (FIG. 13A). [0134] The JC-1 staining was further verified under super resolution confocal microscopy and the results were similar to the flowcytometry (FIG.13B). Overall, these results indicate that the Covid N and S generated the production of ROS and disrupted the MMP, and GGTI298 reduced the ROS production and reverted the MMP. [0135] FIGS. 14A to 14D show the effect of BT881 on reduced mitochondrial function in oxygenated (FIG.14A) and non-oxygenated (FIG. 14B) conditions. FIGS.14C and D show the effect of BT881 that reduced mitochondrial function in oxygenated (FIG. 14C) and non- oxygenated (FIG.14D) conditions. [0136] Example 5. Effect of KLF2 on arresting the cell cycle. [0137] Previous studies demonstrated that KLF2 mediates cells senescence (40). The inventors examined how KLF2 regulates the cell cycle in Covid N and S transfected lymphoid cells. These findings showed that the number of Covid N and S transfected lymphoid cells were significantly higher in G2/M phase of the cell cycle compared to empty vector transfected cells, however, after addition of GGTI298 to Covid N and S transfected cells, the number of G2/M cells were significantly decreased. Now, the cell population were shifted to the G1 phase which became prominent. Next, the inventors investigated the molecular mechanism by which this cell cycle arrest was mediated, and the inventors found that the activation of DNA damage checkpoint molecule ATR and its downstream target, check point molecule, CHK1 in Covid N and S transfected cells, whereas induction of KLF2 markedly reduced the level of checkpoint molecule). These data confirmed that KLF2 mediated arrest of the cell cycle at G1 phase through reduction of checkpoint proteins. [0138] Example 6. Effect of KLF2 on autophagy and upstream signaling pathway molecules. [0139] Autophagy acts as a critical regulator during Covid pathogenesis, as shown in the differential gene expression data analysis (FIGS. 15A-15D). Here, the inventors determined the effect of BT881 on the expression of some important autophagic molecules such as Beclin1, ATG7, and LC3B after the transfection of Covid N and S in K562 cells using qRT-PCR, and cytochemical staining under super resolution confocal microscopy, and western blot methods. These results showed that after the transfection of Covid N and S, the expressions of Beclin1, ATG7, and LC3B were increased significantly, and upon the addition of BT881, the autophagy markers were significantly decreased (FIG. 15A). During the analysis of downstream signaling pathways using ICC and WB, the inventors found that the AKT, cJun, Stat3 and pp38 were activated after the transfection of Covid N and S in K562 cells. However, the addition of BT881 significantly downregulated the above-mentioned molecules (FIGS.15B). [0140] Example 7. Effect of KLF2 on induced fibrosis in lung fibroblast cells. [0141] As fibrosis plays a critical role in Covid morbidity, the inventors examined whether GGTI298 controls the fibrosis. The inventors determined the effect of BT881 on the expression level of some critical fibrosis-associated molecules such as α-SMA, COL1A1, COL3A1, and COL8A1 after the induction (TGF-β-mediated) of fibrosis in lung fibroblast cells (MRC5) using a quantitative RT-PCR method. These results showed that the TGF-β stimulated MRC5 cells had significantly higher expression of all the fibrosis-associated molecules, and significantly lower expression of KLF2. However, after the addition of BT881 during the induction of fibrosis significantly downregulated the fibrosis-associated molecules, and drastically upregulated the expression of KLF2 (FIG.16A). To confirm the expression of genes that translated to the protein level, the inventors performed immunofluorescence studies using a super resolution confocal microscopy, and WB methods, and found that the addition of BT881 significantly inhibited the expression of the α-SMA, COL1A1, COL3A1, and COL8A1 with respect to induced fibrosis in the lung fibroblast cells (FIGS.16B, 16C). These results validate that the KLF2 has the power to nullify the fibrosis process that causes severe morbidity to the Covid infected patients (41). FIG. 16D is a Western blot that shows that BT881 reduced lung fibrosis-related protein markers. [0142] Example 8. In silico modeling of interaction between GGTI298, KLF2 agonists, and Covid spike and nucleocapsid proteins. [0143] To determine how KLF2 reduces pathogenesis of Covid such as cytokine storm and fibrosis the inventors conducted the molecular docking analysis of BT881 and Covid Spike and nucleocapsid protein separately. [0144] FIGS. 17A and 17B show an in silico analyses for the interaction of BT881 with Covid spike and nucleocapsid proteins. FIG. 17Ai-iv. 3D ribbon representation of BT881-Covid S complex. FIG. 17A(i). 3D zoomed image of BT881-Covid S complex. FIG. 17A(ii). 2D representation of BT881-Covid S complex. FIG. 17A(iii). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of Covid S. FIG. 17A(iv). FIG. 17Bi-iv. 3D ribbon representation of BT881-Covid N complex. FIG.17B(i).3D zoomed image of BT881-Covid N complex. FIG.17B(ii). 2D representation of BT881-Covid N complex. FIG. 17B(iii). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of Covid N. FIG. 17B(iv). FIG. 17Ci-iv. 3D ribbon representation of BT881-TGFβR1 complex. FIG. 17C(i). 3D zoomed image of BT881-TGFβR1 complex. FIG.17C(ii).2D representation of BT881-TGFβR1 complex. FIG.17C(iii). Graphical representation of bonding pattern and bond distance occurred between different groups of BT881 and amino acid residues of TGFβR1. FIG.17C(iv). [0145] The elevated cytokine storm and oxidative stress induced by SARS-CoV-2 causes severe pathogenesis and forces hospitalization to ultimately mortality to the patients. Recent studies demonstrated that decrease in KLF2 level is associated with Covid pathogenesis (42, 43). The inventors developed a model of human Covid pathogenesis in lymphoid cells, K562 by transfecting them with Covid N and S plasmid constructs. The Covid pathogenesis in Covid N and S transfected K562 cells was confirmed by examining the expression level of factors associated with cytokine storm, that is manifested by elevated levels of proinflammatory molecules such as interleukins (ILs), IFN ^, TNF ^, and matrix metalloproteinases (MMPs) and lower level of anti-inflammatory molecules such as IL-4, and IL-10. At the same time, the inventors found that the expression of KLF2 was decreased in Covid N and S transfected cells. These data corroborated with the previous studies which demonstrated that COVID-19 patient- serum-treated human endothelial cells exhibited the downregulation of KLF2, and elevated level of endothelial inflammation (44). These data demonstrate that the in vitro Covid model developed herein mimics with human Covid pathogenesis. [0146] To establish the role of KLF2 during Covid Pathogenesis, the inventors took advantage of differential gene expression analysis of Covid-infected patients and healthy individuals using the GEO database # GSE157103. Analyzed data confirmed that the key genes of inflammation and autophagy-associated molecules, and their upstream signaling molecules, were upregulated during Covid pathogenesis. This data also indicated that the downregulation of KLF2 is strongly associated with the induction of inflammation and autophagy. [0147] To further validate the role of KLF2 during Covid pathogenesis, the inventors examined the expression of proinflammatory and anti-inflammatory molecules in Covid N and S in transfected cells after the addition of chemical inducer of KLF2, GGTI298. It was found that addition of GGTI298 reinstates the expression of proinflammatory and anti-inflammatory molecules as well as KLF2 in Covid N and S in transfected cells, which was similar to empty vector transfected control cells. [0148] Oxidative stress and inflammation are interwoven processes that eventually cause the multiorgan failure during Covid progression (45). It is well documented that during Covid infection, elevated levels of ROS mediate the upregulation of nitric oxide synthase, which, in turn, further stimulates the inflammatory pathways (46). The inventors demonstrated that the ROS, both intracellular and mitochondrial was significantly increased after transfection of Covid N and S in the cells. These findings were also similar to the previously reported human pathological conditions, where a significant increase in ROS resulted in the development of oxidative stress leading to cell and tissue damage (47). However, the inventors found that the induction of KLF2 significantly reduced the levels of ROS. [0149] The mitochondria play a prominent role in energy production (49). The inventors examined the mitochondrial membrane potential (MMP), which usually alters during disease conditions. The inventors demonstrated that the mitochondria were depolarized after transfection of Covid N and S in cells while induction of KLF2 restored the MMP by restoring depolarization. It is well established that the oxidative stress causes the mitochondrial dysfunction, which was also found to be critical in the pathogenesis of Covid (50). The inventors assessed the effect of KLF2 on mitochondrial functions, mitochondrial oxidative phosphorylation and glycolysis conditions. These findings showed that the Covid N and S transfected cells with a significantly increased level in both OCR and ECAR bioenergetic parameters, which are in consistent with the pervious observation, demonstrating an increased level in OCR and ECAR parameters after the infection with viral particles expressing the spike protein in hepatocytes (48). However, after induction of KLF2, the inventors found that the bioenergetic parameters of both OCR and ECAR were remarkably reduced resulting in normalizing the function of mitochondria. [0150] Autophagy, an intracellular catabolic process plays a critical role in maintaining intracellular homeostasis by degrading the cellular waste, damaged organs and recycles them through lysosomal process, and dysregulation is associated with various pathogenesis (24-26). Therefore, the inventors examined the autophagy associated markers after transfection of Covid N and S in cells and confirmed the elevated levels of the autophagy molecules. The induction of KLF2 reduced the autophagy associated molecules forcing the infected cells to return into normal state. Furthermore, the inventors determined the upstream pathway signaling molecules, Akt, cJun, Stat3 and P38 to define the signaling cascades during induction of Covid. These findings demonstrated that these molecules were upregulated in the Covid N and S transfected cells while all molecules were downregulated after the induction of KLF2. These data demonstrated that KLF2 negatively regulated the autophagy and inflammation-related pathways. [0151] KLF2 causes cells quiescence (51), as such, the inventors examined the effect of KLF2 on the cell cycle in Covid N and S transfected cells. These findings demonstrated that the cell cycle progression was arrested during the G2/M phase, which is consistent with previous investigations (52). Further, the inventors found that induction of KLF2 arrest the cell cycle at G1 phase of Covid N and S transfected cells through downregulating the DNA damage sensing proteins and checkpoint proteins ATM, ATR, and CHK1. This study was consistent with previous study showing GGTI298 inhibits DNA damage-induced CHK1 expression in embryonic stem cells (53). [0152] During the infection of Covid, proinflammatory molecules, IL-6 activates the IL-6-SIL- 6R-JAK-STAT-3 complexes leading to excessive inflammation of tissues, particularly respiratory tract tissues, resulting in fibrosis and death (54). Numerous studies have demonstrated that TGF- β plays a central role in fibrosis-related diseases (55, 56). To understand the role of KLF2 in overcoming the Covid pathogenesis, the inventors developed a lung fibrosis model using TGF-β stimulation and determined the effect of KLF2 on lung fibrosis. Both the gene expression levels and protein levels of fibrosis markers, such as α-SMA, COL1A1, COL3A1, and COL8A1 were elevated in fibrosis, and induction of KLF2 significantly reduced the fibrosis-related molecules bringing into the normal state. These findings agreed with previous observations that also showed an increased level in KLF2 expression is associated with a reduction in lung fibrosis (57). These findings confirmed that the KLF2 not only diminished cytokine storm but also reduced the fibrosis process, a post-Covid syndrome. [0153] The inventors found that KLF2 mediates the anti-inflammatory and anti-fibrotic properties. To determine this, the inventors took advantage of the system biology approach using the chemical inducer of KLF2, GGTI298, where it binds with SARS-CoV-2 spike and nucleocapsid proteins separately. As KLF2 is a transcription factor and binds to CACCC box of the promoter regions of the target genes; therefore, the inventors used the chemical inducer of KLF2, GGTI298 to understand the exact molecular interaction. Interestingly, it was found that the GGTI298 strongly interacts with both Covid spike and nucleocapsid proteins, proving that the GGTI298 has the efficiency to mitigate the inflammation and fibrosis process which are major factors for the pathogenesis of Covid infection. In sum, these results demonstrated that KLF2 is a prominent target molecule that mediates the reduction of inflammation and fibrosis process, which is a post-Covid syndrome. [0154] Example 9. Development of regenerative therapy for corneal endothelial dystrophies and injuries targeting KLF2. [0155] The present inventors studied the effect of pharmacological compound (BT881) on differentiation of corneal endothelial stem cells. Corneal stem cells are cultured on a normal 10 cm cell culture dish with alpha MEM media and 20% FBS (for control endothelial stem cell culture). When they are grown in stem cells, they are made in only 2% FBS in culture with alpha MEM media. The plate (24 well plate) is then coated with collagen type 1 from BD# 354236 (100mg, 3.4mg/ml concentration). 200uL of this same solution is used, hold for 30 minutes, remove and allow to dry completely. After drying they culture and add corneal endothelial stem cells. BT881 (10uM) is then applied; all there are cultures, one is collagen-coated and one is non- collagen coated and one is fibronectin coated. They keep for three days; after three days, the shape that is seen is the shape of the differentiating cells. Cells become hexagonal in shape and smaller in size; instead of being elongated. The fibronectin used in 0.5mg/mL, collected / isolated from human plasma. Catalog no.5050 from Advanced Biometics. The results are summarized in FIG. 18. [0156] FIG. 18 shows the differentiation of Corneal Endothelial Stem Cells (CESC) to Corneal Endothelial Cells (CEC), in the presence of fibronectin, collagen, and no coating in the presence of BT881. [0157] Further testing and confirmation are shown in FIG.19, instead of BT881, GGTI298 was used as a chemical inducer of KLF2. Also at 10uM concentration. GGPP a KLF2 chemical inhibitor was used as a control. With the GGPP inhibitor, the cell shape does not change; maintaining control shape; with GGPP+GGTI298 (e.g., both inducer and inhibitor), this also showed it did not change; if only inducer is used, shape is changing but it is not exactly similar to BT881; with BT881 it is more physiological and more applicable. Changing the shape of the stem cells leads to differentiation. This is shown in FIGS.20A and 20B. [0158] FIG. 19 shows the differentiation of CESC to CES in the presence and absence of GGTI298 (KLF2 inducer), GGPP (KLF2 inhibitor, the GGTI298 at 10 micromolar, 36 hours. [0159] FIGS.20A and 20B shows that BT881 (FIG.20A) and KLF2 induced with GGTI298 (FIG. 20B) mediated differentiation of CESC to CEC at a concentration of 10 micromolar BT881 in the presence of Type I collagen, collagen at 100 mg, GGTI298 at 3.48 mg/ml concentration. [0160] PCR of differentiation markers. Cells were collected, mRNA isolated, and mRNA were subjected to real time PCR, to evaluate all of corneal endothelial cell markers (e.g. ATP1A1 etc.) Also, did KLF2 expression in all of cells as well. The methodology is summarized in the previous examples. In real time PCR, if these genes are expressed, it is indicative that the cells are differentiating. In FIG. 21B, GGT1298 was used and also induced KLF2 but also all differentiation markers. When GGPP is used, it inhibited. This shows inducers are playing critical role in differentiation. FIGS.21A and 21B shows that BT881 (FIG.21A) and KLF2 (FIG.21B) induces expression of mature corneal endothelial cell markers along with KLF2 at 3 days. FIG. 21B shows that KLF2 induced the expression of mature corneal cell markers and inhibition, and inhibition of KLF2 reduced them. [0161] A Western blot was performed and shows not only gene expression, but that it is also inducing the protein expression of the molecules, further confirmation that not only gene expression is key but gene translation into protein is key. Western blot provides proof that hypothesis that this is mediated through KLF2, inducing into protein expression. FIG.22 shows that BT881 induced expression of mature corneal endothelial cell markers at the protein level. CEC – corneal endothelial marker; CESC – is CE stem cell; Collagen coated + BTT881 is used in FIGS. 22A and 22B; CEC = (CESC + collagen + BT881). These data confirms that the CESC differentiated into CEC by shape changed, gene, and protein expression. [0162] FIG.23 shows that when BT881 + CESC was used, at a cell cycle level, it is showm that the cells are in G1 phase. When BT881 is added, cells are getting blocked or expressing higher in the G1 phase. The number of cells in G1 phase is higher. When the number of cells in G1 phase is increased, is shows the stage of the cell cycle they are getting accumulated, indicating that the cells are differentiating. All of the experiments used the same methods described hereinabove. [0163] FIG.23 shows that BT881 arrested cell cycle at G12 phase during differentiation. [0164] The effect of BT881 was shows using human cells. A stem cell supernatant was collected and used on cells monolayers and a scratch wound assay (using standard protocol) was conducted using the corneal endothelial stem cells in presence or absence of supernatant. Here, tit is shown that the stem cell supernatant also works; thus healing a wound in corneal cells. FIG.24 shows that human Corneal Endothelial Stem Cells (hCESC) accelerated wound healing in HUVEC human endothelial cells. FIG. 25 shows that human Corneal Endothelial Stem Cells (hCESC) accelerated wound healing in bovine endothelial cells. [0165] Next, the inventors show the level of oxidative stress, since oxidative stress is required for cell differentiation. Intercellular stress is detected by DCFDA (a dye that measures intracellular ROS). On left hand side, use CESC, and on right use BT881. With BT881 the stress is increased and cell shape is differentiated and smaller in size, forming a clump. The cells are visualized with confocal microscopy; pictures of the cells taken and cells that are expressing these molecules meaning the DCFDA level is higher. Top green figures, this is confocal microscopy. The confocal microscopy used standard methodology with regard to intracellular dye. Visual on top with confocal microscopy and bottom figures is with flow cytometry. Left is unstained; green is stained control and red is CESC + BT881; graphically shows that it increases. FIG.26 shows that BT881 increased the level of intracellular ROS (2',7'-dichlorofluorescin diacetate (DCFDA)) in CESC. [0166] Next, ROS is measured in mitochondria. The dye used is MitoSOX instead of DCFDA. This dye measures mitochondria; how much mitochondria in the cell affects ROS and this is detected by confocal microscopy and flow cytometry. Not only is mitochondrial ROS increased these data show that BT881 changes the mitochondrial membrane potential showing it is being altered. FIG.27 shows that BT881 increased the level of mitochondrial ROS (mitoSOX) in CESC. [0167] FIG.28 shows that BT881 increased the mitochondrial membrane potential (using JC-1 as the dye) in CESC. [0168] Next, the inventors studies oxygenated conditions (OCR); how mitochondrial respiration is working; CESC in presence of BT881 (red line) – one is control (blue); one is in presence of oxygen (left) and one without (right – in glycolytic conditions; ours can function in both conditions. FIG. 29B and FIG. 29C, show how much difference we are seeing between control and CESC + BT881 in these; all these measurements provide not only are they differentiating but they are functionally active. [0169] FIGS.29A to 29C show a Sea Horse Analysis on CESC to CEC using BT881. FIG.29A shows mitochondrial respiration (oxygen consumption rate) and glycolytic function (extracellular acidification). FIG.29B shows that BT881 increased the mitochondrial respiration (oxygenated) in CESC. FIG.29C shows that BT881 increased the mitochondrial respiration (non-oxygenated) in CESC. [0170] Next, the inventors determined where BT881 is binding. The inventors used in silico analysis (described hereinabove) and a system biology approach, which shows exactly where it is binding in this located. Binding is as shown in the FIGS.30A to 3D. The in silico anlysis shows how BY881 works through differentiation and where it binds to the protein and which amino acids it is binding. [0171] FIGS. 30A to 31D show that BT881 interacts with NF-kappaB (p65) to reduce inflammation. FIG.30A shows a 3D ribbon representation of BT881-NFkappaB (p65) complex. FIG.30B shows a 3D zoomed image of the BT881-NFkappaB (p65) complex. FIG.30C shows a 2D graphical representation of BT881-NFkappaB (p65) complex. FIG.30D shows a graphical representation of bonding pattern and bond distance between BT881 and amino acid residues of NFkappaB (p65). [0172] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention. [0173] It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims. [0174] All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. [0175] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. [0176] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps. In embodiments of any of the compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of” or “consisting of”. As used herein, the phrase “consisting essentially of” requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention. As used herein, the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only. [0177] The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context. [0178] As used herein, words of approximation such as, without limitation, “about”, "substantial" or "substantially" refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present. The extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature. In general, but subject to the preceding discussion, a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%. [0179] Additionally, the section headings herein are provided for consistency with the suggestions under 37 CFR 1.77 or otherwise to provide organizational cues. These headings shall not limit or characterize the invention(s) set out in any claims that may issue from this disclosure. Specifically, and by way of example, although the headings refer to a “Field of Invention,” such claims should not be limited by the language under this heading to describe the so-called technical field. Further, a description of technology in the “Background of the Invention” section is not to be construed as an admission that technology is prior art to any invention(s) in this disclosure. Neither is the “Summary” to be considered a characterization of the invention(s) set forth in issued claims. Furthermore, any reference in this disclosure to “invention” in the singular should not be used to argue that there is only a single point of novelty in this disclosure. Multiple inventions may be set forth according to the limitations of the multiple claims issuing from this disclosure, and such claims accordingly define the invention(s), and their equivalents, that are protected thereby. In all instances, the scope of such claims shall be considered on their own merits in light of this disclosure, but should not be constrained by the headings set forth herein. [0180] For each of the claims, each dependent claim can depend both from the independent claim and from each of the prior dependent claims for each and every claim so long as the prior claim provides a proper antecedent basis for a claim term or element. [0181] To aid the Patent Office, and any readers of any patent issued on this application in interpreting the claims appended hereto, applicants wish to note that they do not intend any of the appended claims to invoke paragraph 6 of 35 U.S.C. § 112, U.S.C. § 112 paragraph (f), or equivalent, as it exists on the date of filing hereof unless the words “means for” or “step for” are explicitly used in the particular claim. [0182] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the invention. 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Claims

What is claimed is: 1. A molecule selected from at least one of formula: ;

2. A method of treating a musculoskeletal disorder in a subject comprising: identifying that the subject has a musculoskeletal disorder; and providing a therapeutically effective amount of a molecule selected from at least one of:

; ; ; or salts thereof, wherein the molecule reduces at least one of osteoclast differentiation or inflammation.

3. The method of claim 2, wherein the musculoskeletal disorder is selected from at least one of arthritis, rheumatoid arthritis (juvenile and adult), synovitis, osteoarthritis, degenerative joint disease, connective tissue diseases, polymyalgia rheumatica, ankylosing spondolytis, polymyositis, bursitis, fibromyalgia, gout, neuralgia, chronic fatigue syndrome, osteoporosis, and bone damage from cancer metastasis to the bone.

4. The method of claim 2, further comprising one or more pharmacologically acceptable excipients, fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver.

5. The method of claim 2, wherein the molecule is formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration.

6. The method of claim 2, wherein the molecule is formulated for sustained release, controlled release, delayed release, suppository, catheter, or sublingual administration, or direct injection.

7. The method of claim 2, wherein the molecule is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days. 8. The method of claim 2, wherein the molecule is administered at a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day; preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; more preferably 1.5-2.5 mg/day; 1.5 mg/day, 2.0 mg/day or 2.5 mg/day. 9. The method of claim 2, wherein the molecule is administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg,

8 mg,

9 mg or 10 mg; or 4.5-7.5 mg/day.

10. The method of claim 2, wherein the molecule is administered by infusion.

11. The method of claim 2, wherein the molecule is administered by infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion.

12. The method of claim 2, wherein the molecule is administered using a loading dose and a maintenance dose.

13. The method of claim 2, wherein the molecule is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions.

14. A pharmaceutical composition comprising: a molecule selected from at least one of:

; ; ; and one or more pharmaceutical acceptable excipients or salts.

15. The composition of claim 14, wherein the one or more pharmaceutical acceptable excipients or salts are selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver.

16. The composition of claim 14, wherein the molecule(s) is/are formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration.

17. The composition of claim 14, wherein the molecule(s) is/are formulated for sustained release, controlled release, delayed release, suppository, catheter, or sublingual administration, or direct injection.

18. The composition of claim 14, wherein the molecule(s) is/are administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days.

19. The composition of claim 14, wherein the molecule(s) is/are administered at a dose of 5 mg a day or less, 4.5 mg a day or less, 4 mg a day or less, 3.5 mg a day or less, 3 mg a day or less, 2.5 mg a day or less or 2 mg a day or less; 0.5 mg/day, 1 mg/day, 1.5 mg/day, 2 mg/day, 2.5 mg/day, 3 mg/day, 3.5 mg/day, 4 mg/day, 4.5 mg/day, or 5 mg/day; preferably 1 mg/day, 1.5 mg/day, 2 mg/day or 2.5 mg/day; more preferably 1.5-2.5 mg/day; 1.5 mg/day, 2.0 mg/day or 2.5 mg/day.

20. The composition of claim 14, wherein the molecule(s) is/are administered at a total dose of 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5- 10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day.

21. The composition of claim 14, wherein the molecule(s) is/are administered by infusion.

22. The composition of claim 14, wherein the molecule(s) is/are administered by infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion.

23. The composition of claim 14, wherein the molecule(s) is/are administered using a loading dose and a maintenance dose.

24. The composition of claim 14, wherein the molecule(s) is/are formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions.

25. A method of preventing or treating a cytokine storm triggered by a coronavirus 2 (SARS- CoV-2) infection in a subject, the method comprising administering to the subject a therapeutically effective amount of an agonist of Kruppel-like factor 2 (KLF2).

26. The method of claim 25, wherein the subject has been diagnosed with COVID-19.

27. The method of claim 25, wherein the KLF2 agonist is a vector that expresses KLF2 or increases the expression of KLF2.

28. The method of claim 25, wherein the KLF2 agonist is formulated with one or more pharmaceutical acceptable excipients or salts selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver.

29. The method of claim 25, wherein the KLF2 agonist is formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration.

30. The method of claim 25, wherein the KLF2 agonist is formulated for sustained release, controlled release, delayed release, suppository, catheter, sublingual administration, or direct injection.

31. The method of claim 25, wherein the KLF2 agonist is administered once daily, once weekly, twice weekly, once every 14 days, or once monthly.

32. The method of claim 25, wherein the KLF2 agonist is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days.

33. The method of claim 25, wherein the KLF2 agonist is administered at a total dose of 1- 50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day.

34. The method of claim 25, wherein the KLF2 agonist is administered by infusion.

35. The method of claim 34, wherein the infusion is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion.

36. The method of claim 25, wherein the KLF2 agonist is administered using a loading dose and a maintenance dose.

37. The method of claim 25, wherein the KLF2 agonist is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non- aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions.

38. The method of claim 25, wherein the KLF2 agonist reduces morbidity or mortality in the clinical course of COVID19, reduces symptoms caused by SARS-CoV-2, or reduces the need for ventilator dependency.

39. The method of claim 25, wherein the KLF2 agonist results in a decrease in one or more symptoms related to acute respiratory distress syndrome (ARDS).

40. The method of claim 39, wherein the one or more symptoms related to the ARDS is selected from the group consisting of a feeling that one cannot get enough air into the lungs, rapid breathing, low oxygen levels in the blood, and clicking, bubbling, or rattling sounds in the lungs when breathing.

41. The method of claim 25, wherein the KLF2 agonist is administered in combination with a second therapeutic.

42. The method of claim 41, wherein the second therapeutic is an antiviral drug, an antimalarial drug, an anti-inflammatory drug, an antibiotic, an acid-reducing medicine, a blood thinner, a muscle relaxant, a pain reliever, a sedative, or a diuretic.

43. A method of treating fibrosis in a subject, the method comprising administering to the subject a therapeutically effective amount of an agonist of Kruppel-like factor 2 (KLF2).

44. The method of claim 43, wherein the KLF2 agonist is a vector that expresses KLF2 or increases the expression of KLF2.

45. The method of claim 43, wherein the KLF2 agonist is formulated with one or more pharmaceutical acceptable excipients or salts selected from one or more pharmacologically acceptable fillers, buffers, solvent, water, diluent, an absorption or penetration enhancer, preservative, antioxidant, chelating agent, ion exchange agent, solubilizing agent, suspending agent, thickener, surfactant, wetting agent, tonicity-adjusting agent, enzyme inhibitor, or vehicle for proper drug deliver.

46. The method of claim 43, wherein the KLF2 agonist is formulated into a pharmaceutical dosage form that is adapted for oral administration, intravenous administration, intraperitoneal administration, transdermal administration, intrathecal administration, intramuscular administration, intranasal administration, transmucosal administration, subcutaneous administration, or rectal administration.

47. The method of claim 43, wherein the KLF2 agonist is formulated for sustained release, controlled release, delayed release, suppository, catheter, sublingual administration, or direct injection.

48. The method of claim 43, wherein the KLF2 agonist is administered once daily, once weekly, twice weekly, once every 14 days, or once monthly.

49. The method of claim 43, wherein the KLF2 agonist is administered according to a regimen of a daily dose for 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day; preferably 2-5 days, 3-5 days, or 3, 4 or 5 days; 3 days or 5 days; or 3 days.

50. The method of claim 49, wherein the KLF2 agonist is administered at a total dose of 1- 50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 3-15 mg, 3-12 mg, 4-12 mg, 4-10 mg, or 4.5-10 mg; 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg; preferably 4.5 mg, 5 mg, 6 mg, 7.5 mg, 8 mg, 9 mg or 10 mg; or 4.5-7.5 mg/day.

51. The method of claim 43, wherein the KLF2 agonist is administered by infusion.

52. The method of claim 51, wherein the infusion and is a 1 hour infusion, a 1.5 hour infusion, a 2 hour infusion, a 3 hour infusion, a 4 hour infusion, a 5 hour infusion, a 6 hour infusion, a 7 hour infusion, an 8 hour infusion, or a 12 hour infusion.

53. The method of claim 43, wherein the KLF2 agonist is administered using a loading dose and a maintenance dose.

54. The method of claim 43, wherein the KLF2 agonist is formulated into a dosage form selected from tablets, soft gelatin capsules, hard gelatin capsules, sugar-coated tablets or pills, powders or granulates; juices, syrups, drops, teas, solutions or suspensions in aqueous or non- aqueous liquids; edible foams or mousses; or in oil-in-water, or water-in-oil in emulsions.

55. The method of claim 43, wherein the fibrosis is lung fibrosis, kidney fibrosis, liver fibrosis, or cardiac fibrosis post-infection with SARS-CoV-2.

56. A method of preventing or treating corneal epithelial dystrophies, wound healing, and injuries with a Kruppel-like factor 2 (KLF2) agonist, the method comprising: obtaining or having obtained one or more corneal epithelial stem cells (CESC); contacting the CESC with an amount of a KLF2 agonist sufficient to differentiate the CESC into corneal epithelial cells for form differentiated corneal epithelial cells; and administering to a subject in need thereof with a therapeutically effective amount of the differentiated corneal epithelial cells sufficient to prevent or treat the corneal epithelial dystrophies, wound healing, and injuries.

57. The method of claim 56, wherein the KLF2 agonist is selected from at least one of: ;

; or salts thereof.

58. The method of claim 56, wherein the KLF2 agonist is provided in an amount sufficient to increase would healing.

59. A method of preventing or treating cytokine storm, fibrosis, or both with a Kruppel-like factor 2 (KLF2) agonist, the method comprising: obtaining or having obtained one or more stem cells; contacting the stem cells with an amount of a KLF2 agonist sufficient to differentiate the stem cells to form KLF2 differentiated stem cells; and administering to a subject in need thereof with a therapeutically effective amount of the differentiated KLF2 differentiated stem cells sufficient to prevent or treat cytokine storm, fibrosis, or both.

60. The method of claim 56, wherein the KLF2 agonist is selected from at least one of: ;

; or salts thereof.

61. The method of claim 56, wherein the KLF2 agonist is provided in an amount sufficient to reduce cytokine storm in coronavirus infection.