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. 2024 Nov 15:278:116808.
doi: 10.1016/j.ejmech.2024.116808. Epub 2024 Aug 30.

Inhibitor of the non-structural protein 2 protease shows promising efficacy in mouse models of chikungunya

Damilohun S Metibemu  1 , Olawale S Adeyinka  1 , John Falode  1 , Tamia Hampton  1 , Olamide Crown  1 , J Chinenye Ojobor  1 , Aarthi Narayanan  2 , Justin Julander  3 , Ifedayo Victor Ogungbe  4
Affiliations

Inhibitor of the non-structural protein 2 protease shows promising efficacy in mouse models of chikungunya

Damilohun S Metibemu et al. Eur J Med Chem. .

Abstract

Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.

Keywords: CHIKV; Chikungunya; Covalent inhibitors; Non-structural protein; Vinyl sulfone; nsP2 protease.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ifedayo Victor Ogungbe reports financial support was provided by National Institute of Allergy and Infectious Diseases. Ifedayo Victor Ogungbe reports a relationship with Biomolecular Science, LLC that includes: equity or stocks. Ifedayo Victor Ogungbe has patent Covalent inhibitors of equine encephalitis virus granted (US Patent 11,905,249) to Jackson State University. N/A If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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