# Targeting the UL37 deamidase to impede HSV-1 infection.

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $248,875

## Abstract

ABSTRACT
Herpesviruses are ubiquitous human pathogens worldwide. Though herpesvirus infections are
often asymptomatic in normal individuals, they cause significant morbidity and mortality in
immune-compromised individuals. Antivirals have been successfully developed to target the viral
thymidine kinase for the past nearly half-century. In the presence of such antivirals, drug-
resistance of herpes simplex viruses (HSV), including HSV-1 and HSV-2, is rapidly emerging,
particularly in those immune-compromised individuals such as AIDS patients. Thus, new antivirals
are desperately needed to cope with the dire situation.
We have previously identified the HSV-1 UL37 deamidase that deamidates and inactivates
cytosolic RIG-I and cGAS, thereby muting host innate immune defense. The enzymatic activity of
UL37 represents an “Achilles heel” that can be targeted to restore host immune defense.
Continuing our original discoveries on protein deamidation, we synthesized series of glutamine
analogues to identify inhibitors of selected protein deamidases. In this study, we have identified
three lead compounds that selectively inhibit UL37-mediated protein deamidation, but not those
mediated by cellular deamidases. Ground on these preliminary results, we will characterize the
mode of action of these UL37 inhibitors in protein deamidation and innate immune response
during HSV-1 infection. We will further employ a combination of mass spectrometry, structural
and pharmacological analysis to improve these lead compounds via iterative synthesis and
functional assays. The resulted best inhibitors will be assessed by pharmacokinetics and
pharmacodynamic studies as well as antiviral efficacy using mouse model. This pilot study will
not only provide proof-of-concept to counteract HSV-1 infection via inhibiting a viral deamidase
and restoring host immune defense, but also develop important tools that enable further
investigation into protein deamidation in fundamental biological processes.

## Key facts

- **NIH application ID:** 10789647
- **Project number:** 1R21AI180537-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Pinghui Feng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,875
- **Award type:** 1
- **Project period:** 2024-05-14 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789647

## Citation

> US National Institutes of Health, RePORTER application 10789647, Targeting the UL37 deamidase to impede HSV-1 infection. (1R21AI180537-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10789647. Licensed CC0.

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