# Project 5: Pandemic Virus Helicase Inhibitors

> **NIH NIH U19** · UNIVERSITY OF MINNESOTA · 2022 · $456,759

## Abstract

Project 5 – Pandemic Virus Helicase Inhibitors
ABSTRACT
The goal of this project is to develop pan-family, antiviral drug candidates targeting the viral helicase of
coronavirus and flavivirus. All priority RNA viruses encode a viral helicase domain in their genomes, and they
share high similarity in structure and biochemical features. Viral RNA helicase is a critical component of the viral
replicase complex and is essential for RNA virus replication. Further, it shows a high sequence homology within
the virus family (e.g., 100% identity within SARS2). Consequently, viral RNA helicases can serve as a novel
antiviral target for RNA viruses with a high barrier to drug resistance. During the past 10 years, the Chung lab
has made significant contributions to the development of antivirals targeting the alphavirus helicase domain
(nsP2) and validated viral helicase as druggable for developing potent antivirals. Based on this success, we
hypothesize the viral helicase can serve as a valid target for safe and effective antivirals for SARS2 and other
priority RNA viruses.
Here, we propose a comprehensive antiviral discovery campaign targeting viral helicase with a multi-disciplinary
approach combining ultra-high-throughput screening and DNA-Encoded Chemistry Technology followed by a
robust hit validation scheme with antiviral testing, structural biology, and biochemical approaches (Aim 1).
Further, we propose to advance promising viral helicase inhibitor hits through hit-to-lead development, giving
validated leads as drug development candidates with medicinal chemistry paired with AI-based drug design,
DMPK studies, and in vivo antiviral efficacy studies (Aim 2). Finally, we will deliver 1-2 orally bioavailable,
patentable, druglike IND-enabled small molecules (a development candidate + backup) that are well-suited for
translation by a pharma partner (Aim 3). Our proposal is supported by our discovery of a novel hit compound
(UNC0379) with an anti-SARS2 activity from a pilot 100,000-compound library screen (Core B). The PI and
established team (Chung, virology/PI; Bannister, Med. Chem/deputy; Spicer, uHTS; Luo, structural biology of
viral replicase; Raney, helicase biochemistry) synergistically combine antiviral drug discovery (Head-Gordon,
Compchem/AI) with excellent core support (Core B and Core C). Our effort will deliver new classes of direct
helicase-targeting antiviral agents for SARS2 infection and other high priority viral pathogens.

## Key facts

- **NIH application ID:** 10674237
- **Project number:** 3U19AI171954-01S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Donghoon Chung
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $456,759
- **Award type:** 3
- **Project period:** 2022-05-16 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10674237

## Citation

> US National Institutes of Health, RePORTER application 10674237, Project 5: Pandemic Virus Helicase Inhibitors (3U19AI171954-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10674237. Licensed CC0.

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