# Development of Broad-Spectrum Antiviral Therapeutics by Destabilizing the Main Protease of Coronaviruses

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $427,052

## Abstract

Abstract
At the moment, there is a worldwide outbreak of coronavirus disease 2019 (COVID-19) that is caused by the
infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We urgently need effective
anti-viral therapeutics against SARS-CoV-2 and related coronaviruses to avoid potential future outbreaks. This
proposal seeks pilot funding to support the interdisciplinary collaboration between medicinal chemists and
virologists to develop novel small molecules that can destabilize 3-chymotrypsin like protease (3CLpro), the
main viral protease that is essential for the replication of SARS-CoV-2 and many related coronaviruses. The
proposed small molecules are able to catalyze the degradation of 3CLpro through the host cell’s ubiquitin-
proteasome-system, which routinely removes damaged or unfolded proteins.
The proposed degraders are bifunctional molecules with a short linker between two ligands. One ligand binds
with high selectivity to an E3 ubiquitin ligase while the other ligand simultaneously engages the viral protein
target. As the binding event occurs, the viral protein is brought in close contact with the E3 ubiquitin ligase
complex and is poly-ubiquitinated for degradation in the proteasome. The degrader is then released to
continue its catalytic activity for the degradation of the viral protein. The degrader only needs to bind transiently
to the target viral protein to induce its ubiquitination, which offers many advantages over traditional small
molecule inhibitors.
We selected 3CLpro as the primary target for selective degradation based on its key role in viral replication and
the availability of selective inhibitors, which will serve as the ligand that binds to 3CLPro. Although inhibitors for
3CLpro exist, degraders’ catalytic properties will render them much more potent. By destabilizing and
destroying the viral protein instead of stoichiometrically binding to the viral protein, degraders should also act
faster than inhibitors. 3CLpro is conserved among many coronaviruses including SARS-CoV, MERS-CoV, and
SARS-CoV-2. The proposed small molecule degraders can be potent antiviral therapeutics against a broad
spectrum of coronaviruses, including viral strains that are resistant to antiviral inhibitors. In aim 1, we will
prepare bifunctional small molecule degraders by linking ligands of E3 ligase and 3CLPro using our recently
developed two-stage strategy. In aim 2, we will evaluate the degradation and anti-viral activities of 3CLPro
degraders in cell-based assays.
The research groups of PI and Co-Investigator are highly experienced in bifunctional small molecule degrader
development and anti-viral research, respectively. The proposed study will produce important proof-of-concept
data for the development of novel antiviral therapeutics against SARS-CoV-2 and related coronaviruses.

## Key facts

- **NIH application ID:** 10177321
- **Project number:** 1R21AI158210-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Weiping Tang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,052
- **Award type:** 1
- **Project period:** 2020-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177321

## Citation

> US National Institutes of Health, RePORTER application 10177321, Development of Broad-Spectrum Antiviral Therapeutics by Destabilizing the Main Protease of Coronaviruses (1R21AI158210-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10177321. Licensed CC0.

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