# Accelerated development of advanced leads against SARS-CoV-2 and other pandemic viruses

> **NIH NIH U19** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2022 · $3,885,770

## Abstract

Abstract
There is an urgent need for a safe, highly effective orally bioavailable drug that can be used in the outpatient
setting. Ideally, such drugs would have broad-spectrum potential and would be activity against SARS-CoV-2
and other existing and potentially future emergent coronaviruses. A viable strategy to accelerate drug
development is repositioning of approved drug and/or existing clinical candidates as chemical scaffolds to create
new chemically optimized clinical development candidates. Working in partnership with a team of drug hunters
at Merck, focused compound libraries derived from existing antiviral classes discovered/developed against
other conserved viral targets and new Lead series to both host and viral targets were screened. The most
promising candidates were found to target the main (3CL or MPro) protease. The 3CLpro inhibitors being
optimized are peptidyl mimetics of the active site amino acid substrates that were derived from an initial hit
boceprevir. Boceprevir is an HCV NS3 protease inhibitor developed by Merck as the first direct acting antiviral
used to treat HCV-infection. Initial structure-based optimization of 3CLpro was used to increase analog potency
>170-fold relative to the parent compound. Program protease inhibitors now under optimization represent
multiple distinct sub-series of new chemical entities. To aid in this process, a robust cell-based SARS-CoV-2
replicon system was established to rapidly evaluate compounds for potency. Lead compounds with inhibitory
activity of <10 nM were identified following detailed dose response in EC50,90/CC50 studies yielding
therapeutic index ratios >1000. The compounds have suitable pharmacologic development properties and are
candidates for animal efficacy studies. The objective of this program is to establish Optimized Leads suitable
as oral drug candidates to enter IND enabling studies by 1) finalizing Leads for in vitro potency (IC90 <10 nM;
EC50 <10 nM) and safety (CC50 >10 µM) with high therapeutic index >1000; and in vivo lung efficacy against
SARS-CoV-2 (TCID50 >5 logs) and other coronaviruses; 2) define PK/PD Relationships, tolerability, resistance,
and pre-IND considerations, and 3) perform IND-enabling and de-risking studies. This Program takes advantage
of the Merck’s team expertise in developing antiviral drugs and the MAVDA in providing high-end Core support
for animal models, resistance assessment, and access to viral models beyond SARS-CoV-2.

## Key facts

- **NIH application ID:** 10513922
- **Project number:** 1U19AI171401-01
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** David S Perlin
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,885,770
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513922

## Citation

> US National Institutes of Health, RePORTER application 10513922, Accelerated development of advanced leads against SARS-CoV-2 and other pandemic viruses (1U19AI171401-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10513922. Licensed CC0.

---

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