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

Autor:	Adeyinka OS; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Barrera MD; Department of Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States., Metibemu DS; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Boghdeh N; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.; Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Manassas, Virginia 20109, United States., Anderson CA; Department of Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States., Baha H; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States., Crown O; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Falode JA; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Bleach JL; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.; Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Manassas, Virginia 20109, United States., Bliss AR; School of Systems Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States.; Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Manassas, Virginia 20109, United States., Hampton TP; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Ojobor JC; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States., Alem F; Biomedical Research Laboratory, Institute for Biohealth Innovation, George Mason University, Manassas, Virginia 20109, United States., Narayanan A; Department of Biology, College of Science, George Mason University, Fairfax, Virginia 22030, United States., Ogungbe IV; Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2024 Dec 31. Date of Electronic Publication: 2024 Dec 31.
DOI:	10.1021/acsinfecdis.4c00701
Abstrakt:	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.
Databáze:	MEDLINE
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