Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of <i>Chikungunya</i> nsP2 Cysteine Protease with Antialphavirus Activity
Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (<b>1a</b>) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of <b>1a</b> that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of <i>Chikungunya</i> (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 (<b>1o</b>) and 4-cyanopyrazole (<b>8d</b>) analogs exhibited <i>k</i><sub>inact</sub>/<i>K</i><sub>i</sub> ratios >9000 M<sup>-1</sup> s<sup>-1</sup>. 3-Arylisoxazole (<b>10</b>) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like <b>1a</b>. A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.
Authors
- Kesatebrhan Haile Asressu (ORCID: https://orcid.org/0000-0003-4803-4739)
- Sumera Perveen (ORCID: https://orcid.org/0000-0002-8898-9540)
- John D. Sears (ORCID: https://orcid.org/0000-0002-4713-2241)
- Mark T. Heise (ORCID: https://orcid.org/0000-0001-5829-8477)
- Kenneth H. Pearce (ORCID: https://orcid.org/0000-0001-8138-5421)
- Anirban Ghoshal (ORCID: https://orcid.org/0000-0001-9359-6074)
- Eric M. Merten (ORCID: https://orcid.org/0000-0002-5306-0790)
- Nathaniel J. Moorman (ORCID: https://orcid.org/0000-0003-4952-6858)
- Isabella Law
- Konstantin Popov (ORCID: https://orcid.org/0000-0001-6034-7143)
- Meganathan Nandakumar (ORCID: https://orcid.org/0000-0002-9093-2244)
- Timothy M. Willson (ORCID: https://orcid.org/0000-0003-4181-8223)
- Mohammad Anwar Hossain (ORCID: https://orcid.org/0000-0001-8684-8755)
- Peter J. Brown (ORCID: https://orcid.org/0000-0002-8454-0367)
- Anand Vala (ORCID: https://orcid.org/0000-0002-2186-820X)
- Jane Burdick (ORCID: https://orcid.org/0009-0001-9719-8302)
- Noah L. Morales
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Toronto (CA)
- Structural Genomics Consortium (CA)
- Piramal (India) (IN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01346
- Citations
- 25
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 13.57
Funders
- Bristol-Myers Squibb
- Pfizer
- Bayer
- North Carolina Biotechnology Center
- McGill University
- Genome Canada
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Ontario Genomics Institute
- University of Toronto
- National Institutes of Health
- Genentech
- University of North Carolina at Chapel Hill
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill