# Novel Anti-HCMV Strategies

> **NIH NIH R01** · UPSTATE MEDICAL UNIVERSITY · 2021 · $722,643

## Abstract

PROJECT SUMMARY
Human cytomegalovirus (HCMV) is the single most important infection leading to transplant failure and
continues to be a cause of substantial morbidity and death. Indeed, HCMV disease occurs in 20-30% of
transplants at risk for infection and is a particular problem to lung or heart-lung recipients with a reported
incidence of 50-80%. Clinical manifestations of HCMV are widespread, inflammatory in nature, and dependent
on end-organ dysfunction. Inflammatory organ diseases associated with a HCMV infection is a direct
consequence of the systemic viral spread to and infection of multiple organ sites that occur during either
asymptomatic or symptomatic infections. Monocytes are responsible for delivering the virus into tissue and
play a central role in the inflammatory state of infected organs. Since therapies against HCMV are designed to
block specific steps along the virus replication cycle, the lack of HCMV replication in infected blood monocytes
indicates that HCMV antiviral drugs are not effective in preventing the initial spread of the virus. In accord,
prophylaxis has simply shifted the kinetics of HCMV disease to later after transplantation due to the inability of
antiviral drugs to eliminate infiltrating infected inflammatory myeloid cells, which are the principle cell type
found in infected organs of transplant patients. Thus, we advocate that the suppression of HCMV replication
with prophylactic antiviral drugs must be administered in combination with novel drugs specifically capable of
killing infected monocytes. We have found that HCMV explicitly utilizes cellular Mcl-1, an antiapoptotic
member of the Bcl-2 family of proteins, to stimulate the survival of infected monocytes. Using a high-
throughput screening approach, Dr. Nikolovska-Coleska’s laboratory has synthesized and characterized two
novel classes of highly selective Mcl-1 antagonists. We have tested one lead compound from each class of
inhibitor and demonstrated both to have high killing activity towards HCMV-infected monocytes. Furthermore,
we were able to significantly enhance the selectivity and killing activity of each compound by encapsulation into
nanoparticles developed in Dr. Luo’s laboratory. Thus, we hypothesize that Mcl-1 inhibitors will target HCMV-
infected monocytes to prevent hematogenous dissemination, which will be tested in 3 separate aims. Aim 1
will further evaluate the two library classes of Mcl-1 small-molecule inhibitors to identify compounds exhibiting
maximum cytotoxicity against HCMV-infected monocytes. Medicinal chemistry will also be preformed to
increase the potency of compounds. Aim 2 will be to further develop and characterize nanoparticle technology
to enhance targeting of Mcl-1 inhibitors towards infected monocytes. Aim 3 will determine the efficacy of free
versus encapsulated Mcl-1 small-molecule inhibitors at neutralizing/limiting HCMV spread in a humanized
mouse model. These studies will evaluate the use of Mcl-1 inhibitors as an...

## Key facts

- **NIH application ID:** 10140408
- **Project number:** 5R01HL139824-04
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Gary Ching Tao Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $722,643
- **Award type:** 5
- **Project period:** 2018-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140408

## Citation

> US National Institutes of Health, RePORTER application 10140408, Novel Anti-HCMV Strategies (5R01HL139824-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140408. Licensed CC0.

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