# Small Molecule Protease Inhibitors against MERS-CoV and Coronaviruses of Pandemic Potential

> **NIH NIH R01** · KANSAS STATE UNIVERSITY · 2024 · $773,323

## Abstract

PROJECT SUMMARY
 Middle East respiratory syndrome coronavirus (MERS-CoV) emerged suddenly in 2012 as the cause of
severe respiratory illness in humans. Despite the high mortality rate (~ 40%) and the significant potential for a
public health emergency, there are no FDA-approved vaccines or antiviral drugs for MERS. Consequently, there
is an urgent and unmet need for the development of small-molecule drugs to control MERS-CoV infection.
Furthermore, members of the Merbecovirus and Sarbecovirus subgenera within the Betacoronavirus genus pose
a high risk of future spillover into humans. However, efforts to develop general strategies to mitigate the impact
of future pandemics have been limited. Coronavirus 3C-like protease (3CLpro) is a well-characterized
therapeutic target as it processes most cleavage sites on virus polyproteins and is essential for virus replication.
Multiple series of 3CLpro inhibitors with potent activity against MERS-CoV and in vivo efficacy in mouse models
were reported by our group. However, these compound series are parenterally administrable with limited oral
bioavailability. Hypothesize of this project is that inhibitors exploiting the exquisite stereochemical control and
multiple diversity sites afforded by the 1,3,2-oxazaphospholidin-3-one scaffold (series I and II) and decorated
with a novel transition state analog endowed with favorable oral bioavailability can serve as a launching pad for
the development of orally bioavailable MERS-CoV-specific antivirals. As these inhibitors can engage in binding
interactions with the Sn and Sn' pockets of various coronavirus 3CLpros, the scaffold provides a versatile platform
for merbecoviruses and sarbecoviruses. Aims of this project are 1) Conduct iterative structure-guided design,
synthesis, and multiparameter optimization of inhibitors for MERS-CoV; 2) Conduct biochemical, structural, and
virological studies to characterize and prioritize analogs for MERS-CoV 3CLpro and conduct structure-activity
relationship studies with the generated series for merbecovirus/sarbecovirus 3CLpros; and 3) Demonstrate in
vivo efficacy of optimized leads in a mouse model of MERS-CoV infection. The overarching goal of this project
is the identification of an orally bioavailable preclinical candidate and 1-2 backup compounds based on inhibitor
series (I and II) for MERS-CoV infection, and the exploration and utilization of the generated inhibitors against
the 3CLpros of merbecoviruses and sarbecoviruses.

## Key facts

- **NIH application ID:** 10978461
- **Project number:** 2R01AI130092-06
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **Principal Investigator:** Kyeong-Ok Chang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $773,323
- **Award type:** 2
- **Project period:** 2024-07-19 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978461

## Citation

> US National Institutes of Health, RePORTER application 10978461, Small Molecule Protease Inhibitors against MERS-CoV and Coronaviruses of Pandemic Potential (2R01AI130092-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10978461. Licensed CC0.

---

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