# Research Project 1: Coronavirus antiviral lead development and combination testing

> **NIH NIH U19** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $5,087,610

## Abstract

ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 has
profoundly impacted global human health and shown that it is imperative to develop antivirals for prevention and
treatment of CoVs that are targeted to key required CoV replication functions and are orally available. The highly-
collaborative CoV research programs in the Denison lab at Vanderbilt University Medical Center (VUMC) and
the Sheahan and Baric labs at UNC Chapel Hill have been world leaders for over 30 years on CoV replication,
evolution, pathogenesis, and countermeasures. Our programs led IND-enabling preclinical studies for the
nucleoside analog antivirals remdesivir (RDV) and molnupiravir (MPV). For the current proposed READDI-AC
AVIDD program, Project 1 (VUMC-Denison PI) and Project 2 (UNC-Sheahan PI) will pursue parallel but highly
integrated antiviral discovery and development projects focused on distinct replicase functions. Project 1 (this
project) will focus on the two essential virus encoded proteases nsp3-papain like protease (nsp3-PLPro) and
nsp5-3C-like protease or main protease (nsp5-3CLPro / Mpro), while Project 2 will target antiviral development
for the nsp12-RNA-dependent RNA polymerase and nsp13-helicase. For Project 1, we have assembled a team
with deep experience and achievement in state-of-the-art drug design and chemistry, drug development,
coronavirus protease biology, and in vivo models of human CoV (HCoV) infection from academia, industry and
multiple-program Cores. The overall goal of Project 1 is to discover and develop direct-acting, orally-available,
potent and broad-spectrum antivirals targeting CoV proteases and design combinations that boost activity and
prevent the emergence of resistance against SARS-CoV-2 and other emerging coronaviruses. Studies in Aim 1
will discover and validate hits and prioritize and optimize lead compounds. For nsp5-3CLPro, we will initiate
studies with established lead compounds from Pardes Biosciences. For nsp3-PLPro we use validated hits and
ongoing discovery from a fragment-structure-based screening approach. We will determine activity, breadth, and
toxicity of compounds in high-throughput virological assays and optimize uptake and metabolic profile of leads.
Aim 2 will use lead compounds to define the genetic basis for viral resistance, viral fitness of resistance mutants,
and mechanism of action. We will test leads from Project 1 in combination with other protease inhibitors,
nucleoside analogs (RDV, MPV), and leads from Project 2. In Aim 3, we will optimize the in vivo PK/PD of
chemical leads, determine the efficacy of optimized leads against SARS-CoV-2 and other CoV in vivo, determine
the effect of resistance on in vivo efficacy, and test the efficacy of combinations. We already have a panel of
lead compounds and validated hits from partners against both nsp5-3CLPro and nsp3-PLpro that will enter the
pipeline in Aims 2 and 3, as well as multiple early hit candidate...

## Key facts

- **NIH application ID:** 10513684
- **Project number:** 1U19AI171292-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Ralph S Baric
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $5,087,610
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513684

## Citation

> US National Institutes of Health, RePORTER application 10513684, Research Project 1: Coronavirus antiviral lead development and combination testing (1U19AI171292-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10513684. Licensed CC0.

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