# Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

> **NIH NIH R21** · JACKSON STATE UNIVERSITY · 2022 · $178,590

## Abstract

Project Summary
Emerging viral infections caused by mosquito-borne alphaviruses such as Venezuelan/West-
ern/Eastern equine encephalitis virus (VEEV, EEEV or WEEV) and Chikungunya virus are loom-
ing threats to public health systems around the world. There are no vaccines or therapeutics ap-
proved for human use against alphaviruses, and we have limited understanding of the molecular
pathogenicity of most alphaviruses. If regional or transnational outbreak of alphavirus infections
occur in the future, loss of life and loss of economic productivity can be minimized or prevented
if therapeutic or prophylactic agents are available. In this application, we propose an investiga-
tion into a new series of molecules that inhibit the protease domain of the non-structural protein
2 (nsP2) of VEEV, blocks the replication of VEEV in human cells, and are amenable to systematic
structural changes that is important for drug development. The main goals of this project are: (a).
To investigate covalent and mechanism-based reversible inhibitors of nsP2 using multiparameter
structure-activity studies relationships (SAR) studies along with complementary metabolic and
bioavailability studies; and (b). To investigate the molecular interactions between the molecules
and nsP2 using crystallography and molecular modelling, which will facilitate target-specific op-
timization of drug lead candidates. The project goals will facilitate the advancement of the com-
pound series towards preclinical investigation as first-in-class nsP2 inhibitors that have anti-al-
phaviral activities at physiologically relevant concentrations. Additionally, the molecules will
also serve as valuable molecular tools to advance our understanding of the role of nsP2 in the
pathogenicity of alphaviruses.

## Key facts

- **NIH application ID:** 10476358
- **Project number:** 5R21AI159740-02
- **Recipient organization:** JACKSON STATE UNIVERSITY
- **Principal Investigator:** JOSEPH A WHITTAKER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $178,590
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476358

## Citation

> US National Institutes of Health, RePORTER application 10476358, Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease (5R21AI159740-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10476358. Licensed CC0.

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