# Novel small-molecule inhibitors of SARS-CoV-2 protease

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2021 · $440,000

## Abstract

The overall objective of this project is to use a combination of medicinal chemistry, X-ray crystallography,
biochemical and biological activity testing to develop potent, drug-like inhibitors of the main protease (Mpro) of
SARS-CoV-2 (SARS-2), a novel coronavirus that causes an outbreak of a serious pulmonary disease COVID-
19 (coronavirus disease 2019). SARS-2 has emerged in Wuhan, China and soon spread to >210 countries
worldwide. WHO has declared COVID-19 a global pandemic in March 11, 2020. As of early June, SARS-2 has
infected ~7 million people (confirmed cases) globally, including ~2 million cases in the US. These numbers are
rapidly growing everyday. SARS-2 is highly contagious. While most patients (81%) infected with SARS-2 show
relatively mild symptoms, life-threatening severe illness, including severe pneumonia, sepsis and organ failure,
can occur at a significantly higher risk for people at age of ≥65 years and people with serious underlying
medical conditions. SARS-2 has caused ~400,000 deaths globally including >110,000 in the US (as of early
June, 2020), which makes it one of the most dangerous pathogens in modern history. There is therefore a
pressing need to find effective therapeutics and vaccines for SARS-2 infection. The main protease (Mpro) of
SARS-2 is essential for the viral replication and therefore a drug target. Specific Aim 1 is to use ration inhibitor
design, medicinal chemistry and structure-activity relationship (SAR) studies to find more potent inhibitors of
SARS-2 Mpro. Specific Aim 2 is to perform enzyme inhibition, X-ray crystallographic and other
biochemical/physical studies to characterize compounds made in Aim 1, which will be used to guide rational
design and SAR studies in Aim 1 to find compounds with improved potency. Specific Aim 3 is to perform
cytotoxicity and cellular antiviral activity testing of selected potent inhibitors of SARS-2 Mpro, in order to find
non-cytotoxic, potent antiviral compound against SARS-2 and -1 infections. Success of this pilot project would
lead to small-molecule inhibitors with improved potency that can strongly inhibit SARS-2 replication. In
addition, X-ray crystallography and other biochemical/physical studies would reveal the inhibitor-Mpro
interactions. These compounds would serve as novel pharmacological leads for further drug development
targeting SARS-2 and other coronavirus infection.

## Key facts

- **NIH application ID:** 10200270
- **Project number:** 1R21AI159323-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Yongcheng Song
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,000
- **Award type:** 1
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200270

## Citation

> US National Institutes of Health, RePORTER application 10200270, Novel small-molecule inhibitors of SARS-CoV-2 protease (1R21AI159323-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10200270. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*