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WO2022078536A1 - Combinaison de substances pour l'inhibition de protéases à cystéine virales - Google Patents

Combinaison de substances pour l'inhibition de protéases à cystéine virales Download PDF

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Publication number
WO2022078536A1
WO2022078536A1 PCT/DE2021/000142 DE2021000142W WO2022078536A1 WO 2022078536 A1 WO2022078536 A1 WO 2022078536A1 DE 2021000142 W DE2021000142 W DE 2021000142W WO 2022078536 A1 WO2022078536 A1 WO 2022078536A1
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WO
WIPO (PCT)
Prior art keywords
cov
viral
bat
substance combination
hcov
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DE2021/000142
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German (de)
English (en)
Inventor
Monika Aparecida CORONADO
Raphael Josef EBERLE
Dieter Willbold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forschungszentrum Juelich GmbH
Original Assignee
Forschungszentrum Juelich GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forschungszentrum Juelich GmbH filed Critical Forschungszentrum Juelich GmbH
Publication of WO2022078536A1 publication Critical patent/WO2022078536A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines

Definitions

  • FIG. 4 shows a number of fluorescence spectra of SARS-CoV-2 3CL per , which were recorded under the influence of different substance concentrations of suramin (Graph A) and quinacrine (Graph C).
  • FIG. 4 also shows binding saturation curves created for this purpose in order to determine the respective dissociation constant KD.
  • the abscissas (X axes) of the fluorescence spectra indicate the wavelengths in nm at which the fluorescence intensities were measured.
  • the arrow running from top to bottom in graphs A and C in FIG. 4 indicates the associated added substance concentration (0 to 48 pmol/L) of the active substance quinacrine/suramin for the individual fluorescence spectra recorded.
  • the ordinates (Y-axes) indicate the respectively measured fluorescence intensities in relative fluorescence units.
  • the arrows marked with an asterisk, which run parallel to the abscissa in graphs A and C, indicate the shift in the fluorescence maximum caused by the active substance.
  • FIG. 4 Graph C Fluorescence spectrum of SARS-CoV-2 3CL pro under the influence of quinacrine titration. Quinacrine causes a “blue edge excitation shift” of the visible Trp (*).
  • FIG. 4 Graph D A KD value could be determined with the aid of a binding saturation curve and a modified Hill equation SARS-CoV-2 3CL per -quinacrine interaction.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une combinaison des substances suramine et quinacrine pour inhiber les protéases à cystéine virales, plus particulièrement pour inhiber les protéases 3CL virales, et l'utilisation de ladite combinaison de substances pour produire un inhibiteur pour les protéases à cystéine virales, plus particulièrement les protéases 3CL. L'invention concerne également une combinaison de substances pour le traitement d'une infection virale dans un organisme, plus particulièrement pour le traitement d'une infection par des virus de la famille des coronaviridae, et la combinaison de substances en tant que médicament dans le traitement d'infections virales, plus particulièrement dans le traitement d'une infection par des virus de la famille des coronaviridae.
PCT/DE2021/000142 2020-10-14 2021-08-27 Combinaison de substances pour l'inhibition de protéases à cystéine virales Ceased WO2022078536A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102020006305.5 2020-10-14
DE102020006305.5A DE102020006305A1 (de) 2020-10-14 2020-10-14 Stoffkombination zur Inhibierung von viralen Cysteinproteasen

Publications (1)

Publication Number Publication Date
WO2022078536A1 true WO2022078536A1 (fr) 2022-04-21

Family

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Family Applications (1)

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PCT/DE2021/000142 Ceased WO2022078536A1 (fr) 2020-10-14 2021-08-27 Combinaison de substances pour l'inhibition de protéases à cystéine virales

Country Status (2)

Country Link
DE (1) DE102020006305A1 (fr)
WO (1) WO2022078536A1 (fr)

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
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MA CSACCO MDHURST BTOWNSEND JAHU YSZETO T ET AL.: "Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease", CELL RES, vol. 30, no. 8, 2020, pages 678 - 692, XP037208260, DOI: 10.1038/s41422-020-0356-z
MARINHO EMANUELLE MACHADO ET AL: "Virtual screening based on molecular docking of possible inhibitors of Covid-19 main protease", MICROBIAL PATHOGENESIS, ACADEMIC PRESS LIMITED, NEW YORK, NY, US, vol. 148, 30 June 2020 (2020-06-30), XP086352584, ISSN: 0882-4010, [retrieved on 20200630], DOI: 10.1016/J.MICPATH.2020.104365 *
MOTULSKY HCHRISTOPOULOS A: "Fitting models to biological data using linear and nonlinear regression: a practical guide to curve fitting", 2004, OXFORD UNIVERSITY PRESS
ROY ALIM LSRIVASTAVA SLU YSONG J: "Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants", PLOS ONE, vol. 12, 2017, pages e0180632
SALGADO-BENVINDO ET AL.: "Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle", ANTIMICROB. AGENTS CHEMOTHER, vol. 64, no. 8, 2020, pages e00900 - 20, XP055766432, DOI: 10.1128/AAC.00900-20
SERI JO ET AL: "Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 35, no. 1, 1 January 2020 (2020-01-01), GB, pages 1539 - 1544, XP055739978, ISSN: 1475-6366, DOI: 10.1080/14756366.2020.1801672 *
SHAIKH SMTSEETHARAMAPPA JASHOKA SKANDAGAL PB: "A study of the interaction between bromopyrogallol red and bovine serum albumin by spectroscopic methods", DYES PIGMENTS, vol. 73, 2007, pages 211 - 216, XP005650337, DOI: 10.1016/j.dyepig.2005.11.008
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WU QYJIANG LLYANG SGZUO YWANG ZFXI Z ET AL.: "Hexahydrophthalimide-benzothiazole hybrids as a new class of protoporphyrinogen oxidase inhibitors: synthesis, structure-activity relationship, and DFT calculations", NEW J. CHEM., vol. 38, no. 9, 2014, pages 4510 - 4518
YIN WANCHAO ET AL: "Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin", NAT. STRUCT. MOL. BIOL, vol. 28, no. 3, March 2021 (2021-03-01), pages 319 - 325, XP037407902, ISSN: 1545-9993, DOI: 10.1038/S41594-021-00570-0 *
ZHANG LLIN DKUSOV YNIAN YMA QWANG JDE WILDE A: "a-Ketoamides as broadspectrum inhibitors of coronavirus and enterovirus replication: Structure-based design, synthesis, and activity assessment", J. MED. CHEM., vol. 63, 2020, pages 4562 - 4578, XP055806728, DOI: 10.1021/acs.jmedchem.9b01828
ZHANG LLIN DSUN XCURTH UDROSTEN CSAUERHERING L ET AL.: "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors", SCIENCE, vol. 368, no. 6489, 2020, pages 409 - 412, XP055814007, DOI: 10.1126/science.abb3405
ZHU WEI ET AL: "Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-Throughput Screening", ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, vol. 3, no. 5, 4 September 2020 (2020-09-04), pages 1008 - 1016, XP055847027, ISSN: 2575-9108, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acsptsci.0c00108> DOI: 10.1021/acsptsci.0c00108 *

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