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Structure Activity of ß-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Anti-alphavirus Activity.
Ghoshal, Anirban; Asressu, Kesatebrhan Haile; Hossain, Mohammad Anwar; Brown, Peter J; Merten, Eric M; Sears, John D; Perveen, Sumera; Pearce, Kenneth H; Popov, Konstantin I; Moorman, Nathaniel J; Heise, Mark T; Willson, Timothy M.
Afiliación
  • Ghoshal A; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Asressu KH; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hossain MA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Brown PJ; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Merten EM; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Sears JD; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Perveen S; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Pearce KH; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Popov KI; UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Moorman NJ; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Heise MT; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • Willson TM; READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
bioRxiv ; 2024 Jun 13.
Article en En | MEDLINE | ID: mdl-38915519
ABSTRACT
Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic ß-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 three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog 8d exhibited a kinact /Ki ratio >10,000 M-1s-1. 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like 1a. The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos