# Identification of human cytomegalovirus life cycle stage-specific therapeutics

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $396,177

## Abstract

Research Summary
Human cytomegalovirus (CMV) is a -herpes virus that increases morbidity and mortality of
immunocompromised individuals such as newborns, transplant recipients, AIDS patients, and the elderly.
Common manifestations of CMV disease in some immunocompromised hosts include neuronal defects in
infants and gastrointestinal disorders, pneumonia, CMV syndrome, and end-organ disease in transplant
recipients. CMV is the leading cause of birth defects affecting 1-2.5% of newborns with approximately 40,000
new cases of CMV infection annually in the United States and range from 8-50% of solid organ transplant
recipients (>145,000 globally) present with CMV-associated diseases. The anti-CMV FDA-approved drugs,
ganciclovir, valganciclovir, foscarnet, cidofovir, and recently letermovir demonstrate limited efficacy and have
severe drawbacks including poor oral bioavailability, dose-related toxicity, and promote the selection of drug
resistant viral, respectively. CMV is a major health challenge that requires the development of a multi-faceted
approach for the generation of effective and safe treatments to limit CMV proliferation. The objective of the
current grant is to develop and utilize high throughput CMV infectivity assays to identify chemical inhibitors that
target the diverse steps of CMV life cycle. Our central hypothesis is that compounds targeting the multiple
steps of the virus life cycle can be developed into effective therapeutics that block infection, replication, and
dissemination. The CMV life cycle (~96hrs) is a complex process requiring viral factors to manipulate cellular
pathways to generate an infectious particle for dissemination by cell-free infections or cell-to-cell spread. To
identify inhibitors of the different steps of the virus life cycle, we will use CMV variants that express two life-
cycle stage-specific reporter proteins fused to yellow fluorescent protein (YFP): 1) the immediate early (IE)-2
gene product (AD169IE2-YFP), and 2) the early membrane protein unique short (US) 28 in a clinical-like strain
(TB40/EUS28-YFP). In collaboration with Microbiotix, we plan to Aim 1: Perform a high content screening assay to
identify inhibitors of the early steps of a CMV infection; Aim 2: Develop and apply high-throughput screening
assays for the identification of inhibitors of the late stages phases of infection and viral spread; Aim 3: Validate
and prioritize confirmed hits based on potency, specificity, and drug-like properties using a panel of orthogonal
assays; and Aim 4: Define the mechanism of action for prioritized hit compounds. The development and
utilization of several robust high-throughput assays will discover novel compounds that target multiple steps of
the CMV life-cycle. The identified hit compounds have the potential to be developed into lead probes for CMV
infection and dissemination. The prioritized inhibitors would limit CMV infection and dissemination in patients at
risk for CMV-associated diseases.

## Key facts

- **NIH application ID:** 10443755
- **Project number:** 5R01AI139258-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Domenico Tortorella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,177
- **Award type:** 5
- **Project period:** 2019-07-22 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443755

## Citation

> US National Institutes of Health, RePORTER application 10443755, Identification of human cytomegalovirus life cycle stage-specific therapeutics (5R01AI139258-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443755. Licensed CC0.

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