# Multiplex Small Molecule Discovery to Identify Broad-Acting Viral Protease Inhibitors

> **NIH NIH U19** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2022 · $3,545,618

## Abstract

ABSTRACT
Viral pathogens present a serious health and economic burden to society, yet for the majority of viruses, there
are no approved antiviral compounds. Worse still, this treatment gap continues to widen due to a continuous
stream of emerging viral pathogens (e.g. MERS, Zika, and SARS-CoV-2). The objective of this proposal is to
utilize a high-throughput, multiplexed approach for drug screening in combination with a novel approach to
surveying drug resistant variants to guide the development of broad-acting antivirals with the long-term goal of
bridging the existing antiviral therapeutic gap. Our proposal is based on the central hypothesis that DNA-
barcoding technology coupled with deep mutational scans (DMS) of essential viral proteins can be used to rapidly
search through chemical space and guide the hit-to-lead small molecule discovery process. The rationale
underlying this proposal is that, if successful, we will be able to develop optimized leads that are active against
multiple viruses and robust to viral escape at a fraction of the time, cost, and effort of traditional approaches.
Given the ongoing pandemic and their proven pandemic potential, during the initial stages of our proposal, we
will focus on generating broadly active inhibitors against coronavirus proteases. In later years, we will target
other essential viral proteins (e.g. methyltransferase) and viral families (e.g. Flaviviridae). Our preliminary data
support the feasibility of our approach for screening for inhibitors to dozens of viral proteases at the same time,
along with our ability to characterize the effects of hundreds of mutations on the response of a viral protease to
chemical inhibitors. To achieve our project’s goals, we will pursue the following three aims: 1) Increase the
number of viral targets to be simultaneously screened to ≥100 and perform small molecule screens against them;
2) Test our screening hits against live virus, evolve their potency and drug-like properties, and demonstrate their
in vivo efficacy; and 3) Use comprehensive mutagenesis to understand drug-target interactions and guide our
drug development efforts. This proposal is innovative because it presents a multiplex method of small molecule
screening that increases the quantity and richness of the data obtained. It also develops a method of studying
the response of thousands of mutant variants of essential viral proteins to chemical inhibition, and uses this
information to guide the hit-to-lead optimization process. This work is significant and is expected to have a
positive impact by identifying a set of promising broad-acting protease inhibitors against human and animal viral
pathogens, developing a highly-scalable approach to drug screening, and providing a framework for merging
resistance profiling with structural and medicinal chemistry throughout the drug discovery process.

## Key facts

- **NIH application ID:** 10513925
- **Project number:** 1U19AI171401-01
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** DAVID D HO
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,545,618
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513925

## Citation

> US National Institutes of Health, RePORTER application 10513925, Multiplex Small Molecule Discovery to Identify Broad-Acting Viral Protease Inhibitors (1U19AI171401-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10513925. Licensed CC0.

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