# Inhibitors of SARS-CoV-2 proteases

> **NIH NIH U19** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $1,456,362

## Abstract

Modified Project Summary/Abstract Section 
SARS-CoV-2, belonging to the genus betacoronavirus, encodes two large overlapping polyprotein 
precursors (pp1a and pp1ab), four structural proteins (spike, envelope, membrane, and 
nucleocapsid), and several accessory proteins. The two polyproteins (pp1a/pp1ab) must be cleaved 
into their individual, nonstructural proteins for successful viral replication (1). Two viral proteases are 
essential and responsible for processing the polyproteins: the 3C-like protease (3CL protease; CLpro
also referred to as “main protease”, Mpro) and a papain-like protease (PLpro) (2). Importantly, CLpro
cleaves polypeptides after a glutamine residue in the P1 position of the substrate, which is a unique 
activity not observed in other human proteases and suggests that this viral protease can be 
specifically and selectively inhibited by a small molecule inhibitor (3). PLpro also suppresses the innate 
immune response by removing interfernon-stimulated gene 15 (ISG) from viral and host proteins. 
Therefore, both CLpro and PLpro are important direct-acting targets for oral anti-viral development. We 
will develop drug candidates for each of these targets, from early discovery to late lead optimization. 
In the first aim, we have a non-covalent CLpro where we are in hit to lead chemistry and have 
generated a suitable compound for PK studies to potentially test for in vivo efficacy testing. In the 
second aim we are initiating formal hit assessment on PLpro hit compounds based on HCV drugs and 
other chemical templates with the goal in the end of year 1 to enter formal hit to lead chemistry given 
the overall challenge in the field of drugging this target. Additionally, we plan on screening for novel 
PLpro and CLpro using novel chemical libraries at Scripps using NMR screening and cell-based 
reporter assays. This project attempts to have a balanced portfolio between late-stage preclinical 
drug candidates and novel approaches to these two essential viral drug targets.

## Key facts

- **NIH application ID:** 10514324
- **Project number:** 1U19AI171443-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Arnab Kumar Chatterjee
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,456,362
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514324

## Citation

> US National Institutes of Health, RePORTER application 10514324, Inhibitors of SARS-CoV-2 proteases (1U19AI171443-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10514324. Licensed CC0.

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