2. Academic Validation
  3. nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice

nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice

  • ACS Infect Dis. 2025 Jan 10;11(1):181-196. doi: 10.1021/acsinfecdis.4c00701.
Olawale S Adeyinka 1,  Michael D Barrera 2 3,  Damilohun S Metibemu 1,  Niloufar Boghdeh 3 4,  Carol A Anderson 2 3,  Haseebullah Baha 3,  Olamide Crown 1,  John Adeolu Falode 1,  Janard L Bleach 3 4,  Amanda R Bliss 3 4,  Tamia P Hampton 1,  Jane-Frances Chinenye Ojobor 1,  Farhang Alem 4,  Aarthi Narayanan 2,  Ifedayo Victor Ogungbe 1
Affiliations

Affiliations

  • 1 Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States.
  • 2 Department of Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.
  • 3 School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.
  • 4 Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Manassas, Virginia 20109, United States.
PMID: 39737550 DOI: 10.1021/acsinfecdis.4c00701
Abstract

New World alphaviruses, including Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that cause disease in humans. These viruses are endemic to the western hemisphere, and disease in humans may lead to encephalitis and long-term neurological sequelae. There are currently no FDA-approved vaccines or Antiviral therapeutics available for the prevention or treatment of diseases caused by these viruses. The alphavirus nonstructural protein 2 (nsP2) functions as a protease, which is critical for the establishment of a productive viral Infection by enabling accurate processing of the nsP123 polyprotein. Owing to the essential role played by nsP2 in the alphavirus infectious process, it is also a valuable therapeutic target. In this article, we report the synthesis and evaluation of novel small molecule inhibitors that target the alphavirus nsP2 protease via a covalent mode of action. The two lead compounds demonstrated robust inhibition of viral replication in vitro. These inhibitors interfered with the processing of the nsP123 polyprotein as determined using VEEV TC-83 as a model pathogen and are active against EEEV and WEEV. The compounds were found to be nontoxic in two different mouse strains and demonstrated Antiviral activity in a VEEV TC-83 lethal challenge mouse model. Cumulatively, the outcomes of this study provide a compelling rationale for the preclinical development of nsP2 Protease Inhibitors as direct-acting Antiviral therapeutics against alphaviruses.

Keywords

VEEV; alphaviruses; covalent inhibitors; nonstructural protein; nsP2 protease; vinyl sulfone.

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