# The Development of Reversible Covalent PROTAC Technology as a New Anti-COVID-19 Strategy

> **NIH NIH R21** · TEXAS A&M UNIVERSITY · 2021 · $221,910

## Abstract

PROJECT SUMMARY/ABSTRACT
 The current COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. However, to date,
no effective targeted drug or vaccine has been identified yet. Finding effective targeted treatment options is of
paramount importance. SARS-CoV-2 is an enveloped, positive-sensed RNA virus. Main protease (Mpro), a
cysteine protease, is essential for viral replication and pathogenesis which represents an attractive target for the
development of antiviral drugs against SARS-CoV-2. One of the traditional antiviral strategies is to develop high-
affinity ligands that bind directly to viral proteins and inhibit their functions like SARS-CoV-2 Mpro (SC2Mpro).
However, these occupancy-driven inhibitors may lead to several potential problems such as off-target toxicity,
dose-limiting toxicity, and drug resistance. Thus, there is an urgent need for new antiviral strategies that can
address these challenges by exploiting alternative mechanisms to combat existing CoV pathogens like SARS-
CoV-2. Proteolytic targeting chimaera (PROTAC) is an emerging technology for targeted protein degradation in
drug discovery. PROTACs are event-driven bifunctional small molecules that simultaneously engage an E3
ubiquitin ligase and a target protein to facilitate the formation of a ternary complex, leading to the ubiquitination
and ultimate degradation of the target protein. PROTACs have many potential advantages compared to
traditional occupancy-based inhibitors, including (i) catalytic nature to allow for sub-stoichiometric activity, (ii)
enhanced target selectivity, (iii) high barrier to resistance; and (iv) abrogating all functions of the target protein
and its downstream proteins. On this basis, this proposal provides an innovative anti-CoV strategy: reversible
covalent PROTACs by combination of the advantages of ultra-potent reversible covalent SC2Mpro inhibitors and
event-driven PROTAC technology. The overall goal is to validate degradation of SC2Mpro as a new strategy for
developing COVID-19 drugs with improved selectivity and efficacy. The current proposal is built upon the
preliminary work on the discovery of several potent reversible covalent SC2Mpro inhibitors (lowest IC50 < 10 nM)
and one small-molecule SC2Mpro PROTAC degrader. Encouraged by these exciting preliminary studies, the goal
will be achieved by pursuing the following aims: (1) the development of cellular systems to evaluate degradation
of SC2Mpro; (2) the development of various potent reversible covalent anti-CoV PROTACs targeting SC2Mpro; (3)
the exploration of the relationship between SC2Mpro degradation potencies and anti-SARS-CoV-2 activities of
reversible covalent anti-CoV PROTACs. The successful completion of the proposed study will not only lead to
potent anti-CoV PROTACs with good drug-like properties that can be potentially advanced to pre-clinical
evaluation for treating COVID-19, but also will provide a proof-of-concept study for more broadly developing anti-
CoV PR...

## Key facts

- **NIH application ID:** 10289017
- **Project number:** 1R21AI164088-01
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Shiqing Xu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $221,910
- **Award type:** 1
- **Project period:** 2021-06-25 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289017

## Citation

> US National Institutes of Health, RePORTER application 10289017, The Development of Reversible Covalent PROTAC Technology as a New Anti-COVID-19 Strategy (1R21AI164088-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10289017. Licensed CC0.

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