Title:
STABLE POLYPEPTIDE PROTEIN COVALENT INHIBITOR OF PAPAIN-LIKE PROTEASE (PLPRO) TARGETING 2019 NOVEL CORONAVIRUS
Document Type and Number:
WIPO Patent Application WO/2023/056715
Kind Code:
A1
Abstract:
The present invention provides a stable polypeptide protein covalent inhibitor of papain-like protease (PLpro) targeting 2019 novel coronavirus. The present invention also provides use of the stable polypeptide protein covalent inhibitor in preparing a drug for inhibiting the enzyme activity of PLpro. According to the present invention, a method for forming a single sulfonium salt by reacting methionine-cysteine on polypeptide with a dialkylation reagent is adopted to stabilize the sulfonium salt cyclic peptide targeting PLpro. According to the present invention, a novel stable polypeptide protein covalent inhibitor targeting PLpro is invented by adopting a policy of coupling sulfonium salt-stabilized polypeptide to small molecules. The polypeptide protein covalent inhibitor of the present invention can effectively inhibit the activity of PLpro, thereby blocking the immune escape reaction generated by cutting ISG15 by PLpro.
Inventors:
LI ZIGANG (CN)
YIN FENG (CN)
LIU NA (CN)
ZHANG YICHI (CN)
YIN FENG (CN)
LIU NA (CN)
ZHANG YICHI (CN)
Application Number:
PCT/CN2021/141408
Publication Date:
April 13, 2023
Filing Date:
December 25, 2021
Export Citation:
Assignee:
SHENZHEN BAY LABORATORY PINGSHAN TRANSLATIONAL MEDICINE CENTER (CN)
UNIV PEKING SHENZHEN GRADUATE SCHOOL (CN)
SHENZHEN BAY LABORATORY (CN)
UNIV PEKING SHENZHEN GRADUATE SCHOOL (CN)
SHENZHEN BAY LABORATORY (CN)
International Classes:
C07K5/103; A61K38/07; A61K47/42; A61P31/14
Foreign References:
| CN113735937A | 2021-12-03 | |||
| CN110627871A | 2019-12-31 |
Other References:
DONGYUAN WANG, YU MENGYING, LIU NA, LIAN CHENSHAN, HOU ZHANFENG, WANG RUI, ZHAO RONGTONG, LI WENJUN, JIANG YIXIANG, SHI XIAODONG, : "A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity", CHEM. SCI, vol. 10, no. 19, 25 March 2019 (2019-03-25), pages 4966 - 4972, XP093056677
FU, ZIYANG ET AL.: "The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.", NAT COMMUN., vol. 12, 20 January 2021 (2021-01-20), XP055873050, DOI: 10.1038/s41467-020-20718-8
YAHIRA M BÁEZ-SANTOS ET AL.: "The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.", ANTIVIRAL RESEARCH, vol. 115, 29 December 2014 (2014-12-29), XP029136855, DOI: 10.1016/j.antiviral.2014.12.015
LIU NA, WANG DONGYUAN, LIAN CHENSHAN, ZHAO RONGTONG, TU LICHENG, ZHANG YICHI, LIU JIANBO, ZHU HUILIN, YU MENGYING, WAN CHUAN, LI D: "Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide", CHEMBIOCHEM, JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 22, no. 2, 15 January 2021 (2021-01-15), Hoboken, USA, pages 340 - 344, XP093056679, ISSN: 1439-4227, DOI: 10.1002/cbic.202000473
FU, ZIYANG ET AL.: "The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery.", NAT COMMUN., vol. 12, 20 January 2021 (2021-01-20), XP055873050, DOI: 10.1038/s41467-020-20718-8
YAHIRA M BÁEZ-SANTOS ET AL.: "The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.", ANTIVIRAL RESEARCH, vol. 115, 29 December 2014 (2014-12-29), XP029136855, DOI: 10.1016/j.antiviral.2014.12.015
LIU NA, WANG DONGYUAN, LIAN CHENSHAN, ZHAO RONGTONG, TU LICHENG, ZHANG YICHI, LIU JIANBO, ZHU HUILIN, YU MENGYING, WAN CHUAN, LI D: "Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide", CHEMBIOCHEM, JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 22, no. 2, 15 January 2021 (2021-01-15), Hoboken, USA, pages 340 - 344, XP093056679, ISSN: 1439-4227, DOI: 10.1002/cbic.202000473
Attorney, Agent or Firm:
SHANGHAI XIAOXIANG INTELLECTUALPROPERTY AGENCY CO. (CN)
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