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WO2016110177A1 - Peptide alcalin antibactérien et son ciblage, sa conception et son utilisation - Google Patents

Peptide alcalin antibactérien et son ciblage, sa conception et son utilisation Download PDF

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Publication number
WO2016110177A1
WO2016110177A1 PCT/CN2015/097734 CN2015097734W WO2016110177A1 WO 2016110177 A1 WO2016110177 A1 WO 2016110177A1 CN 2015097734 W CN2015097734 W CN 2015097734W WO 2016110177 A1 WO2016110177 A1 WO 2016110177A1
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Prior art keywords
antimicrobial peptide
peptide
targeted
alkaline
antimicrobial
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English (en)
Chinese (zh)
Inventor
刘秋云
何建国
周文良
翁少萍
邢梦
付敏
彭静立
兰崇峰
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Sun Yat Sen University
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Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of biotechnology, and more particularly to alkaline antimicrobial peptides and their targeted design and applications.
  • Antibiotics are a class of natural or synthetic compounds that kill bacteria or inhibit the growth of bacteria. With the continuous development of science and technology, the definition of antibiotics has been continuously expanded, and anti-microbial compounds, including antifungal compounds, have been included in the scope of antibiotics.
  • antibiotic resistance refers to a decrease in sensitivity to chemotherapeutic drugs such as pathogens and cancer cells.
  • the antibiotic resistance mainly refers to the phenomenon that when the microorganism is exposed to the antibiotic environment, it can still survive and reproduce. The reason for the emergence of drug resistance is that under the pressure of natural selection, the strain with the resistance gene will survive as the dominant strain.
  • These resistance genes are usually present in the plasmid, and for microorganisms (especially bacteria), the resistance gene can be transferred and rapidly replicated by transformation, transduction, etc., so that one colony can quickly acquire resistance.
  • Antibacterial peptides generally carry a positive charge, which has a The bacteria have strong activity and are not easy to produce drug resistance.
  • Antibacterial peptides are generally 10 to 40 amino acids in length, often form membrane channels and often have hemolytic and toxic properties, and lack of targeted antibacterial and anticancer properties. If artificially designed antibacterial peptides, new antibiotic resources can be developed to effectively solve the current medical antibiotic resistance problem.
  • the technical problem to be solved by the present invention is to overcome the defects of hemolytic, membrane permeability and toxicity which the conventional antimicrobial peptide often has, and to provide an alkaline antimicrobial peptide.
  • a second object of the present invention is to provide a targeted design method for the above basic antimicrobial peptide.
  • a third object of the present invention is to provide a targeted antimicrobial peptide designed from the above alkaline antimicrobial peptide, which can be targeted against cancer.
  • a fourth object of the present invention is to provide an application of the above basic antimicrobial peptide or a targeted antimicrobial peptide.
  • alkaline antimicrobial peptide consisting of leucine and lysine, the basic antimicrobial peptide having 12 to 24 amino acids, wherein the proportion of lysine is greater than 33.3% .
  • the basic amino acid (lysine) has a positive charge. Generally, it can bind negative ions such as chloride ions, and some hydrophobic amino acids can bind to the cell membrane, destroy the integrity of the cell membrane, and produce antibacterial and bactericidal effects by changing the membrane permeability. .
  • antibacterial peptides obtained by studying basic amino acids (lysine) and hydrophobic amino acids (leucine) in the prior art, but the design of the antibacterial peptide usually requires consideration of the secondary structure of the peptide, and the secondary structure is also It will affect the activity of the finally synthesized alkaline antimicrobial peptide, which not only increases the synthesis cost of the antimicrobial peptide, but also affects the practical application of the antimicrobial peptide; in addition, the alkaline antimicrobial peptide synthesized by the prior art usually forms a membrane channel, and more It is hemolytic and is not safe to the human body.
  • the ratio of the basic amino acid of the antimicrobial peptide obtained by the invention is greater than 33.3%; at the same time, the alkaline antimicrobial peptide of the present invention is a non-high permeability type peptide (usually low permeability type) and does not cleave human red blood cells. , no hemolysis activity, generally does not form a high-efficiency membrane channel, so it is safe for the human body.
  • the hydrophobic amino acid when the hydrophobic amino acid is placed at one end of the antimicrobial peptide, the antibacterial effect of the alkaline antimicrobial peptide is very good; specifically, the hydrophobic amino acid is located at one end of the alkaline antimicrobial peptide, and the hydrophobic amino acid thereof The number is 3-8.
  • the basic antibacterial peptide of the invention has the composition of trillions, and the design of the antibacterial peptide does not need to consider the secondary structure and physicochemical properties of the amino acid, as long as the amino acid composition and the high basic amino acid ratio are maintained, the activity can be formed high.
  • Alkaline antimicrobial peptide Alkaline antimicrobial peptide.
  • amino acid sequence of the basic antimicrobial peptide is as shown in SEQ ID NOS: 1 to 23.
  • the sequence of the basic antimicrobial peptide is L m (L/K) n , (L/K) n L m , wherein 12 ⁇ n ⁇ 24, m ⁇ 8.
  • the amino acid in the antimicrobial peptide may be D-form or L-form, and may have both L-form and D-form.
  • a targeted antimicrobial peptide obtained by linking any one of the above basic antimicrobial peptides to an antibody complementarity determining region through a plurality of leucine; specifically, the targeted antimicrobial peptide is composed of an antimicrobial peptide -Lo-antibody complementarity determining region; wherein o is the number of leucine, o ⁇ 4.
  • the sequence of the targeted antimicrobial peptide is set forth in SEQ ID NOS: 25-31.
  • antibacterial peptides attached to certain antibody complementarity determining regions become targeted antibacterial peptides, and the antibacterial peptides that do not cleave human red blood cells become targeted antibacterial peptides for lysing human red blood cells. Therefore, appropriate screening should be carried out when developing antibacterial peptide drugs.
  • alkaline antimicrobial peptide and the targeted antimicrobial peptide of the present invention have anti-Escherichia coli (MG1655), Pseudomonas aeruginosa (1.2464, Beijing China General Microbial Culture Collection Management Center), Staphylococcus aureus (ATCC6538), multiple resistance Staphylococcus aureus Y5 (Zhang Ying et al., Molecular typing of Staphylococcus aureus in a food poisoning event, Chinese Journal of Preventive Medicine, 2008, 42(9): 672-676; Ran He et al.
  • MG1655 anti-Escherichia coli
  • Pseudomonas aeruginosa (1.2464, Beijing China General Microbial Culture Collection Management Center
  • Staphylococcus aureus ATCC6538
  • multiple resistance Staphylococcus aureus Y5 Zhang Ying et al., Molecular typing of Staphylococcus aureus
  • the alkaline antimicrobial peptide and the targeted antimicrobial peptide of the present invention can be used for bacteriostatic, and can also be used for preparing bacteriostatic drugs.
  • the above antimicrobial peptides when the number of lysines is equal to or exceeds 50% of the peptide, it is effective against Escherichia coli. Above or below 50%, it is effective against both Staphylococcus aureus and Pseudomonas aeruginosa; antimicrobial peptides between 16 and 24 amino acids in length are effective against the above three bacteria.
  • the alkaline antimicrobial peptide and the targeted antimicrobial peptide of the present invention also have an anticancer effect, and the alkaline antimicrobial peptide and the targeted antimicrobial peptide of the present invention have activity against lung cancer cell A549 and immortalization of SV40 virus.
  • the targeted antibacterial peptide has stronger anticancer activity than the control antibacterial peptide at a lower concentration, especially the antibacterial peptide numbered 59, which kills lung cancer cells in 0.1 mM
  • the efficiency is as high as 100.3%; therefore, the targeted antimicrobial peptide of the present invention can be used for targeting bacteriostatic or directed anticancer, and can also be used for preparing bacteriostatic or anticancer drugs.
  • the number of intermediate leucines was 4. These peptides have stronger carcinostatic activity than the control antimicrobial peptide 2 or the control antimicrobial peptide 11 at a low concentration, and the antibody complementarity determining region is the complementarity determining region 3 and 2 of the antibody of the CD47 protein (Yasufumi Kikuchi, Shinsuke) Uno, Yasuko Kinoshita, et al. HUMANIZED ANTI-C D47ANTIBODY. European Patent Application EP1693385), the sequences are: ARGGYYTYDDWG and YIYPYNDGTKYNEKFKD, respectively.
  • CD47 Human cancer cells tested by scientists all express CD47, which is usually expressed at higher levels (on average about three times higher) than normal cells.
  • the antimicrobial peptide of the present invention is linked to the antibody complementarity determining region of the CD47 protein, and the antimicrobial peptide can be brought to the cancer cell site.
  • the antibody complementarity determining region of the antibacterial peptide of the present invention and the CD47 protein must be linked by a leucine phase, and the inventors have found through experiments that the target formed by the complementarity determining region of the antibody directly linked to the CD47 protein by the basic antimicrobial peptide numbered 2 The antimicrobial peptide (No. 63) completely lost its antibacterial activity.
  • the present invention also provides the use of any of the above alkaline antimicrobial peptides for the preparation of a bacteriostatic or/and anticancer drug; the bacteriostatic effect is inhibition of fungi or/and bacteria; the anticancer is to kill lung cancer cells or Kill immortalized cells.
  • the present invention also provides the use of the targeted antimicrobial peptide for the preparation of a bacteriostatic or/and anticancer drug; the bacteriostatic effect is inhibition of fungi or/and bacteria; the anticancer is to kill lung cancer cells or kill immortalization cell.
  • the present invention has the following beneficial effects:
  • the present invention provides an alkaline antimicrobial peptide composed of leucine and lysine, and the number of amino acids of the basic antimicrobial peptide is 12 to 24, wherein lysine The ratio is greater than 33.3%; the alkaline antimicrobial peptide of the present invention does not consider the secondary structure and physicochemical properties of the amino acid, and the antimicrobial peptide can be arbitrarily combined; it is a non-high permeability type peptide (usually low permeability type) and does not cleave the human body.
  • the bacteriostasis effect the above-mentioned alkaline antimicrobial peptide is made into a targeted antimicrobial peptide, and the efficiency of the targeted antimicrobial peptide in the 0.1 mM lung cancer-killing cell is as high as 100.3%; the antimicrobial peptide or the targeted antimicrobial peptide of the present invention can be used for inhibiting Bacteria and anti-cancer, can be widely used in medical, agricultural, food preservatives and other fields.
  • Figure 1 shows the hemolytic activity of antimicrobial peptides and targeted antimicrobial peptides.
  • Figure 2 is the rate at which 80 ⁇ M different antimicrobial peptides hydrolyze ONPG.
  • Figure 3 is a graph showing the rate at which 80 ⁇ M of different antimicrobial peptides hydrolyze ONPG.
  • Figure 4 shows the results of antibacterial and antimicrobial peptides against multi-drug resistant S. aureus Y5.
  • Figure 5 shows the results of antibacterial activity of antibacterial peptides and targeted antibacterial peptides against Pseudomonas aeruginosa.
  • Figure 6 shows the results of an antibacterial peptide and a targeted antimicrobial peptide against S. cerevisiae INVSc1 inhibition zone.
  • Figure 7 shows the killing effect of antimicrobial peptides and targeted antimicrobial peptides on lung cancer cell line A549.
  • Figure 8 shows the killing effect of antimicrobial peptides and targeted antimicrobial peptides on the human bronchial epithelial cell line 16HBE14o– immortalized with SV40 virus.
  • Figure 9 is a graph showing the killing effect of a targeted antimicrobial peptide on the human bronchial epithelial cell line 16HBE14o- immortalized with the SV40 virus.
  • polypeptide sequence of Table 1 various peptides were synthesized by Shanghai Botai Biotechnology Co., Ltd. by fmoc solid phase synthesis, and purified by RP-HPLC; the polypeptide includes an antimicrobial peptide and a targeted antimicrobial peptide, wherein the targeted antimicrobial peptide is The anti-peptide and antibody complementarity determining regions are obtained by several leucine linkages.
  • the bacteria used were Escherichia coli (MG1655), Pseudomonas aeruginosa (1.2464, Beijing China General Microbial Culture Collection Management Center), Staphylococcus aureus (ATCC6538), multi-drug resistant Staphylococcus aureus Y5 (Zhang Ying et al, together with food Molecular typing of Staphylococcus aureus in poisoning events, Chinese Journal of Preventive Medicine, 2008, 42(9): 672-676; Ran He et al. A combinatorial yeast overlay method for the isolation of antibacterial oligopeptides, Proceedings of the National Academy Of Sciences, India Section B: Biological Sciences, 2014, 84(4): 1069–1075),
  • the minimum inhibitory concentration (MIC) determination process is as follows:
  • Bacterial single colonies were inoculated in a conventional LB liquid medium, cultured at 37 ° C, shaking at 200 rpm for 11 hours overnight, and colony forming units were determined.
  • Each peptide (antibacterial peptide and targeted antimicrobial peptide) was set to four final concentrations: 40 ⁇ M, 80 ⁇ . M, 160 ⁇ M and 320 ⁇ M; each peptide was set to 3 parallels per concentration.
  • control group 2 50 ⁇ l of sterile medium and bacterial solution
  • control group 3 50 ⁇ l of bacterial solution + corresponding amount of DMSO and medium corresponding to the sample
  • control group 4 50 ⁇ l Bacterial solution + corresponding amount of water and medium corresponding to the sample.
  • the OD value was measured at 492 nm and 620 nm with a microplate reader.
  • Inhibition rate% 100 ⁇ [1-(peptide and bacterial liquid experimental group - no bacterial culture control group) / (water or DMSO and bacterial liquid control group - no bacterial culture control group)]
  • Antibacterial peptide treatment The antimicrobial peptide was dissolved in PBS, and finally an antibacterial peptide solution having a final concentration of 40 ⁇ M, 80 ⁇ M, 160 ⁇ M, and 320 ⁇ M was obtained.
  • cecropin 20 ⁇ M, 40 ⁇ M, 80 ⁇ M and 160 ⁇ M cecropin (CecA for short) were mixed with the red blood cell suspension according to the above method, the positive control was 1% Triton X-100; the negative control was PBS solution.
  • the 96-well plate after shaking culture was centrifuged at 2000 rpm for 8 minutes, and 60 ⁇ l of the supernatant was aspirated and transferred to a new 96-well plate, and the OD value at a wavelength of 540 nm was detected by a microplate reader.
  • Permeation percentage (A 540 sample - A 540 negative control) / (A 540 positive control - A 540 negative control) x 100%.
  • --galactosidase is a hydrolase located in the cytoplasm of bacteria that hydrolyzes o-nitrophenyl ⁇ -D-galactopyranoside (ONPG) to galactose and o-nitrophenol (yellow).
  • ONPG o-nitrophenyl ⁇ -D-galactopyranoside
  • a certain amount of ONPG was added to the system, and the degree of hydrolysis of ONPG was determined by measuring the change in the absorbance of the culture solution at 420 nm to determine whether ⁇ -galactosidase hydrolyzes ONPG.
  • the ONPG cannot enter the cell.
  • the culture solution rapidly turns yellow, and the A 420 value rises rapidly in a short time. Therefore, this method can be used to detect the effect of antimicrobial peptides on cell membrane permeability. High membrane permeability indicates that the antimicrobial peptide can form a membrane channel.
  • the permeability experiment process of the present invention is as follows:
  • the final experimental group has a volume of 100 ⁇ l per well, a final peptide concentration of 80 ⁇ M, a final concentration of ONPG of 1.5 mM, and a bacterial concentration of 1 ⁇ 10 7 colony forming units; and the final concentration of the peptide in the experimental group is 40 ⁇ M per well.
  • Peptide-to-multi-drug resistant S. aureus Y5 and Pseudomonas aeruginosa inhibition zone experiments Inoculation of bacterial single colonies in conventional LB liquid medium, shaking at 37 ° C, 200 rpm overnight for 11 hours, and determination of colony forming units .
  • the counted S. aureus Y5 and Pseudomonas aeruginosa (1.2464) bacteria are respectively added, so that the concentration of the bacterial liquid is about 1 ⁇ 10 8 colony forming units/ml. Pour into the plate and cool until completely solidified.
  • S. aureus plates were filled with 40 microliters of 5 mM peptide per well, the negative control was 40 microliters of DMSO/water, and the positive control was 10 microliters of 5 mg/ml Amp + , 30 microliters of water.
  • P. aeruginosa plates were supplemented with 25 microliters of 5 mM peptide per well, the negative control was 25 microliters of water per DMSO, and the positive control was 10 microliters, 5 milligrams per milliliter of Amp + , 15 microliters of water.
  • Table 2 The inhibition zone size of the polypeptide against Staphylococcus aureus and Pseudomonas aeruginosa
  • the diameter of the zone of inhibition does not include the diameter of the puncher; a: ARGGYYTYDDWG is the complementarity determining region of the antibody of CD47 protein; b: YIYPYNDGTKYNEKFKD is the complementarity determining region of the antibody of CD47 protein 2
  • YPD medium glucose 2%, peptone 2%, yeast extract 1%, solid medium plus agar 2%; streak culture S. cerevisiae INVSc1 single colony; inoculate single colonies at 30 ° C shaker for 24 hours and remove Store at 4 ° C; measure colony forming units.
  • YPD medium 1:20
  • the yeast liquid concentration is 1 ⁇ 10 6 /ml.
  • the positive control was 10 microliters, 10 mg/l benomyl + 30 microliters of water.
  • the plate was sealed with a parafilm and placed in a 30 ° C incubator for about 18 hours, photographed and the size of the zone of inhibition was recorded. The results are shown in Figure 6 and Table 3.
  • the diameter of the zone of inhibition does not include the diameter of the puncher; a: ARGGYYTYDDWG is the complementarity determining region of the antibody of CD47 protein; b: YIYPYNDGTKYNEKFKD is the complementarity determining region of the antibody of CD47 protein 2
  • the lung cancer cell line A549 is described in the literature (Lieber M, Smith B, Szakal A et al. A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer, 2006, 17(1): 62-70). Cell culture methods are as described by the American Type Culture Collection. Immortalized human bronchial epithelial cell line 16HBE14o– cells are found in references (Cozens A L, Yezzi M J, Kunzelmann K, Ohrui T, Chin L, Eng K, Finkbeiner W E, Widdicombe J H, and Gruenert D C.” CFTR Expression and chloride secretion in polarized immortal human bronchial epithelial cells.
  • cell viability inhibition rate (%) (control group 492 nm absorbance - experimental group 492 nm absorbance value / control group 492 nm absorbance ⁇ 00%) to calculate the inhibition rate of various peptides on cell viability The results are shown in Figures 7-9.

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Abstract

L'invention concerne un peptide alcalin antibactérien constitué par de la leucine et de la lysine. Le peptide alcalin antibactérien comprend 12-24 acides aminés, la proportion de la lysine étant supérieure à 33,3 %. L'invention concerne également un peptide antibactérien ciblé, formé par la liaison du peptide alcalin antibactérien et de la région de détermination de la complémentarité d'un anticorps via la leucine. Le peptide alcalin antibactérien et le peptide antibactérien ciblé peuvent être utilisés comme agent antibactérien et en cas de résistance d'un cancer.
PCT/CN2015/097734 2015-01-07 2015-12-17 Peptide alcalin antibactérien et son ciblage, sa conception et son utilisation Ceased WO2016110177A1 (fr)

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CN119241726A (zh) * 2024-11-06 2025-01-03 东北农业大学 针对大肠杆菌k88的靶向抗菌肽hi-wk及其制备方法和应用
CN119241727A (zh) * 2024-11-06 2025-01-03 东北农业大学 针对大肠杆菌的靶向抗菌肽swp及其制备方法和应用

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CN104592360B (zh) * 2015-01-07 2018-05-29 中山大学 碱性抗菌肽及其靶向设计和应用
EP3423477B1 (fr) * 2015-06-30 2021-09-29 Chain Antimicrobials OY Nouveaux peptides antimicrobiens, leurs variants et leurs utilisations
CN106589135B (zh) * 2016-11-25 2018-08-28 东北农业大学 一种靶向抗菌肽及其制备方法和应用
CN109705195B (zh) * 2019-01-31 2021-12-14 东北农业大学 一种大肠杆菌靶向抗菌肽ki-qk及制备方法和应用
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CN119241726A (zh) * 2024-11-06 2025-01-03 东北农业大学 针对大肠杆菌k88的靶向抗菌肽hi-wk及其制备方法和应用
CN119241727A (zh) * 2024-11-06 2025-01-03 东北农业大学 针对大肠杆菌的靶向抗菌肽swp及其制备方法和应用

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