# Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $654,500

## Abstract

Project Summary/Abstract
Human cytomegalovirus (HCMV) infection in individuals lacking a fully functioning immune system, such as
newborns and transplant patients, can result in severe and debilitating consequences. The majority of the US
Food and Drug Administration approved anti-HCMV drugs target the viral polymerase and resistance to those
drugs has appeared. Therefore, anti-HCMV drugs from novel targets are needed for use in combination with,
or instead of, current polymerase inhibitors. The long-term goal of this proposal is to develop structurally novel
direct-acting antivirals against HCMV targeting aspects of virus replication outside of those for currently
approved drugs. Towards this end, a viral ATPase/endonuclease (pUL89) critically involved in viral genome
packaging and virus assembly has been chosen as a target for antiviral intervention. The objective of this
investigation is to identify, optimize and characterize pUL89 inhibitor scaffolds. To accomplish these goals,
the following specific aims will be pursued: 1. Develop and implement screening assays to identify pUL89 and
HCMV inhibitors. These assays include biochemical assays for pUL89 function as well as HCMV replication
assays in cell culture. 2. HCMV pUL89 inhibitor hit generation and optimization. Hit generation will center
around the focused screening of in-house synthetic small molecules and select compound libraries.
Confirmed hits will be optimized via analogue synthesis, iterative SAR and in vitro ADME assays to generate
potent inhibitors with favorable physicochemical properties. 3. Characterization of advanced inhibitors using
virological, structural and pharmacokinetic techniques. Optimized inhibitor binding to pUL89 will be analyzed
and refined using structural studies. Detailed virological experiments will be performed to characterize the
mechanism of action, verify the target of these inhibitors and document their ability to work with current FDA
approved drugs and against resistant virus. In addition, in vivo pharmacokinetic parameters of the optimized
inhibitors will be determined and used to improve drug-like properties. At the conclusion of the studies outlined
in this proposal, a better understanding of the mechanism of action and role of pUL89 endonuclease activity
in virus replication will be gained and multiple potent preclinical drug candidates targeting pUL89 will be
developed.

## Key facts

- **NIH application ID:** 10318943
- **Project number:** 5R01AI136982-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Robert James Geraghty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $654,500
- **Award type:** 5
- **Project period:** 2019-01-25 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318943

## Citation

> US National Institutes of Health, RePORTER application 10318943, Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein (5R01AI136982-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10318943. Licensed CC0.

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