# Small Molecule Inhibitors Targeting Adenovirus

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $617,449

## Abstract

PROJECT SUMMARY
Adenovirus (Ad) infection is a significant health risk for immune-compromised pediatric patients, and can lead to
serious complications such as pneumonia, urinary infections and hepatitis. Adenoviruses are endemic in military
recruit populations engaging in basic training installations where they have been implicated in recurring
outbreaks of febrile respiratory disease. A vaccine effective against Ad serotypes 4 and 7 has been licensed by
the FDA, but the long-term availability of this vaccine is unclear, and immunization is not available for the
prevention of infections by other Ad serotypes presenting a serious threat to health, including serotypes 6 and
14 which have caused fatal respiratory disease in both juvenile and adult patients. Cidofovir (CDV, HPMPC), an
acyclic nucleoside phosphonate (ANP) derivative, is approved by the FDA for treatment of CMV retinitis.
Although not approved by the FDA for treatment of Ad infection, it is used frequently in the clinic. CDV has
relatively modest cellular anti-Ad potency due to its limited permeability and must be administered intravenously
due to its low oral bioavailability. A further limitation of CDV is its renal toxicity due to concentration in kidney
tissue. Recently, certain “tunable” prodrugs of CDV and HPMPA synthesized at the Univ. of Southern California
(USC) have been demonstrated to be several orders of magnitude more potent against four Ad serotypes in vitro
and orally effective against Ad6 in a Syrian hamster model. The proposed research will build on these highly
promising preliminary data to elucidate the SAR and mechanism of these active prodrugs and structurally related
derivatives. A series of prodrug analogs will be synthesized having variable structural features in the promoiety
and evaluated for anti-Ad activity vs six virulent Ad serotypes. The analogs will also be compared for stability
and PK characteristics, toxicity in a hamster model, and the most promising prodrugs will be further evaluated
for efficacy against Ad6 in the Syrian hamster model. This research, which will be performed by an
interdisciplinary team led by Prof. Charles McKenna (USC, analog design and synthesis), Prof. Mark Prichard
(Univ. of Alabama-Birmingham, in vitro studies) and Prof. William Wold (Saint Louis University, in vivo studies),
has the ultimate goal of identifying and developing a safe, highly effective oral prodrug of CDV for the treatment
of acute respiratory disease and disseminating infection in immune-compromised individuals.

## Key facts

- **NIH application ID:** 10073466
- **Project number:** 5R01AI135122-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** CHARLES E MCKENNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $617,449
- **Award type:** 5
- **Project period:** 2019-01-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073466

## Citation

> US National Institutes of Health, RePORTER application 10073466, Small Molecule Inhibitors Targeting Adenovirus (5R01AI135122-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10073466. Licensed CC0.

---

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