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Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity.

التفاصيل البيبلوغرافية
العنوان: Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity.
المؤلفون: Ghoshal A; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Asressu KH; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Hossain MA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Brown PJ; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Nandakumar M; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Vala A; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej, Bavla Highway, Ahmedabad, Gujarat 382213, India., Merten EM; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Sears JD; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Law I; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Burdick JE; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Morales NL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Perveen S; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada., Pearce KH; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Popov KI; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Moorman NJ; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Heise MT; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States., Willson TM; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16505-16532. Date of Electronic Publication: 2024 Sep 05.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Antiviral Agents*/pharmacology , Antiviral Agents*/chemistry , Antiviral Agents*/chemical synthesis , Sulfones*/pharmacology , Sulfones*/chemistry , Sulfones*/chemical synthesis , Chikungunya virus*/drug effects , Chikungunya virus*/enzymology , Cysteine Endopeptidases*/metabolism, Structure-Activity Relationship ; Cysteine Proteinase Inhibitors/pharmacology ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/chemistry ; Humans ; Animals ; Virus Replication/drug effects
مستخلص: Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 ( 1a ) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of 1a that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole ( 1o ) and 4-cyanopyrazole ( 8d ) analogs exhibited k inact / K i ratios >9000 M -1 s -1 . 3-Arylisoxazole ( 10 ) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like 1a . A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.
التعليقات: Update of: bioRxiv. 2024 Jun 13:2024.06.12.598722. doi: 10.1101/2024.06.12.598722. (PMID: 38915519)
المشرفين على المادة: 0 (Antiviral Agents)
0 (Sulfones)
EC 3.4.22.- (Cysteine Endopeptidases)
0 (Cysteine Proteinase Inhibitors)
EC 3.4.22.- (nsP2 proteinase)
5PFN71LP8M (divinyl sulfone)
تواريخ الأحداث: Date Created: 20240905 Date Completed: 20240926 Latest Revision: 20240926
رمز التحديث: 20240926
DOI: 10.1021/acs.jmedchem.4c01346
PMID: 39235978
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.4c01346