2. Academic Validation
  3. Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Anti-alphavirus Activity

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

  • bioRxiv. 2024 Jun 13:2024.06.12.598722. doi: 10.1101/2024.06.12.598722.
Anirban Ghoshal 1 2,  Kesatebrhan Haile Asressu 1 2,  Mohammad Anwar Hossain 1 2,  Peter J Brown 1 2,  Eric M Merten 3 2,  John D Sears 4 2,  Sumera Perveen 5,  Kenneth H Pearce 3 2,  Konstantin I Popov 3 2,  Nathaniel J Moorman 4 2,  Mark T Heise 6 4 2,  Timothy M Willson 1 2
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 READDI AViDD Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 3 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.
  • 4 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 5 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
  • 6 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
PMID: 38915519 DOI: 10.1101/2024.06.12.598722
Abstract

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 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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