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nsP2 Protease Inhibitor Blocks the Replication of New World Alphaviruses and Offer Protection in Mice
Olawale S Adeyinka1, Michael D Barrera2,3, Damilohun S Metibemu1
1Chemistry and Biotechnology Science and Engineering Program, College of Science, The University of Alabama in Huntsville, Huntsville, Alabama 35899, United States.
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.
Insights
New small molecule inhibitors targeting alphavirus nsP2 protease show promise for treating Venezuelan equine encephalitis virus (VEEV) and related alphaviruses. These compounds effectively inhibit viral replication and protect mice from lethal challenges.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- New World alphaviruses (VEEV, EEEV, WEEV) are mosquito-borne pathogens causing encephalitis with no approved treatments.
- The alphavirus nonstructural protein 2 (nsP2) protease is essential for viral replication and a key therapeutic target.
Purpose of the Study:
- To synthesize and evaluate novel small molecule inhibitors targeting the alphavirus nsP2 protease.
- To assess the efficacy and safety of these inhibitors against VEEV, EEEV, and WEEV.
Main Methods:
- Synthesis of small molecule inhibitors designed for covalent interaction with nsP2 protease.
- In vitro evaluation of antiviral activity and polyprotein processing inhibition using VEEV TC-83.
- In vivo assessment of compound toxicity and efficacy in a VEEV TC-83 lethal challenge mouse model.
Main Results:
- Two lead compounds demonstrated potent inhibition of viral replication in vitro.
- Inhibitors effectively blocked nsP123 polyprotein processing and showed activity against VEEV, EEEV, and WEEV.
- Compounds were non-toxic in mouse models and provided significant protection against lethal VEEV challenge.
Conclusions:
- Novel nsP2 protease inhibitors exhibit strong antiviral activity against New World alphaviruses.
- These findings support the preclinical development of nsP2 inhibitors as direct-acting antivirals for alphavirus infections.
