# Optimization of novel inhibitors of human cytomegalovirus

> **NIH NIH R56** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $683,995

## Abstract

Summary:
Human cytomegalovirus (CMV) is a β-herpes virus with high seroprevalence rates of 60-90% within the
population that can spread through bodily fluids, organ transplants, and from mother to fetus via the placenta.
Virus proliferation significantly increases the morbidity and mortality of immunocompromised individuals, such
as newborns, organ transplant recipients, AIDS patients, and the elderly. Approximately 30,000 solid organ
transplant and 23,000 bone marrow transplants operations are performed in the U.S. every year. CMV is the
leading cause of birth defects, affecting ~1% of newborns giving rise to ~30,000 new cases of CMV infection
reported annually in the US. While several drugs have been approved by the FDA for the treatment of CMV
infections, including ganciclovir, foscarnet, letermovir, and recently maribavir, these compounds were found to
exhibit high frequencies of drug resistance and severe side effects, including bone marrow toxicity,
gastrointestinal disruption, and nephrotoxicity. Given the large number of patient populations at risk for CMV-
associated diseases and the estimated cost to treat CMV in the US ($4.4 billion/year by the National Academy
of Sciences), novel therapeutic strategies to treat CMV-associated diseases is needed. The development of
novel therapeutics that target different steps of the viral life cycle to limit virus propagation and dissemination
would provide therapeutic for treating CMV-related diseases. We developed a high-content screening assay
using a CMV AD169 reporter virus to screen >112,000 compounds in collaboration with Microbiotix to identify
inhibitors that block the early stage of infection. One compound, MBXC-4302, is a N-arylpyrimidinamine
(NAPA) that exhibited potent anti-CMV infection activity (IC50 ~3 µM), limited cytotoxicity (CC50 >100µM),
favorable in vitro ADME properties, and a responsive structure activity relationship (SAR). Commercial analogs
of MBXC-4302 identified MBXC-4992 with an improved selective index. Our general hypothesis is that the
NAPA compounds represent novel CMV entry inhibitors that can be developed into effective CMV
therapeutics. To evaluate our hypothesis, we plan to complete the following Aims: 1) Characterize the
mechanism of action and broad inhibition of the NAPA compounds; 2) Optimize the NAPA series through SAR-
driven analog generation; 3) Evaluate the ability of NAPA compounds to limit virus proliferation and
dissemination in diverse in vitro models; and 4) Evaluate pharmacokinetics, tolerability, and efficacy of
prioritized NAPA analogs in dissemination studies in vivo. We plan to develop several NAPA analogs as
effective CMV therapeutics that inhibit CMV dissemination as a single agent or in combination with FDA
approved CMV drugs.

## Key facts

- **NIH application ID:** 11125021
- **Project number:** 1R56AI175974-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Domenico Tortorella
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,995
- **Award type:** 1
- **Project period:** 2024-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11125021

## Citation

> US National Institutes of Health, RePORTER application 11125021, Optimization of novel inhibitors of human cytomegalovirus (1R56AI175974-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/11125021. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*