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

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

  • Eur J Med Chem. 2024 Nov 15:278:116808. doi: 10.1016/j.ejmech.2024.116808.
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

Affiliations

  • 1 Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, AL, 35899, USA.
  • 2 Department of Biology, College of Science, George Mason University, Fairfax, VA, 22030, USA.
  • 3 Institute for Antiviral Research and the Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, 84322, USA.
  • 4 Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, AL, 35899, USA. Electronic address: victor.ogungbe@uah.edu.
PMID: 39236495 DOI: 10.1016/j.ejmech.2024.116808
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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