# Project 4: Nuclease Inhibitors for Viruses of Pandemic Concern

> **NIH NIH U19** · UNIVERSITY OF MINNESOTA · 2022 · $3,040,167

## Abstract

Project 4 – Nuclease Inhibitors for Viruses of Pandemic Concern
Abstract
SARS-CoV-2 (SARS2) and highly pathogenic arenaviruses including Lassa virus (LASV), Junin virus, and
Machupo virus share a structurally and functionally related 3'-to-5' exoribonuclease (ExoN) domain, which plays
essential roles in proofreading during RNA syntheses by the error-prone viral RNA-dependent RNA polymerase
(RdRp) and suppressing host antiviral responses. Project 4 is pursuing chemical inhibition of ExoN from these
viruses of pandemic concern, with the goal of blocking viral replication by lethal mutagenesis as well as mitigating
viral pathogenesis by reactivating host’s interferon responses. Our team has contributed extensively to the
structural and functional understanding of these viral ExoN enzymes, including the elucidation of their first atomic
structures and characterization of catalytic mechanisms. We have also developed robust fluorescence-based
assays to quantitatively analyze the ExoN catalytic activities, including a novel assay featuring fluorogenic RNA
aptamer substrates that enables a gain-of-function readout in ultra-high-throughput screening (uHTS).
Furthermore, we have used DNA-encoded chemistry technology (DEC-Tec) to obtain selective binders to
SARS2 ExoN and LASV nucleoprotein (NP) containing the ExoN domain. Building on these prior and preliminary
studies, we will continue to work closely with Core B and use 3 complementary approaches (uHTS, DEC-Tec,
and Virtual screening) to identify first-in-class viral ExoN inhibitors. We will then leverage the deep expertise of
Core C and Core D in medicinal chemistry and structural biology, respectively, to enhance the potency,
selectivity, and pharmacodynamic/kinetic properties of hit compounds for detailed antiviral studies in cell and
animal models by Core E. These studies will deliver antiviral drug candidates with a distinct mechanism of action
to complement those developed against established antiviral targets including RdRp, helping to address the
critical need for novel antiviral drugs against both SARS2 and the highly pathogenic arenaviruses that cause
fatal hemorrhagic fever infections.

## Key facts

- **NIH application ID:** 10522813
- **Project number:** 1U19AI171954-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Hideki Aihara
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,040,167
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522813

## Citation

> US National Institutes of Health, RePORTER application 10522813, Project 4: Nuclease Inhibitors for Viruses of Pandemic Concern (1U19AI171954-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10522813. Licensed CC0.

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