# Anchimerically Activatable Anti-Zika/Dengue ProTides

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $670,946

## Abstract

Arboviruses such as, Dengue (DENV) and Zika (ZIKV), have been associated with several global epidemics.
DENV infections can result in a mild fever to potentially fatal dengue shock syndrome, dengue hemorrhagic fever
and death, while ZIKV infections can result in congenital microcephaly and the development of autoimmune
diseases. Initial clinical manifestation of DENV and ZIKV disease are similar and co-infections have been
reported. Most challenging, DENV and ZIKV are known to co-circulate, increasing the probability of co-infections,
and thus the potential for severe disease. Consequently, since there is no effective vaccine or form of treatment
for either virus, the development of anti-ZIKV and anti-DENV therapeutics is an urgent unmet medical need.
 Over the past decade prodrugs of nucleotides, referred to as ProTides, have been found to have potent
antiviral activity. The anti-hepatitis C virus (HCV) drug sofosbuvir (FDA approved 2013) is the most notable
ProTide success, since its use in combination therapy can clear Hepatis C virus infections. Recently, a similar
ProTide, remdesivir, has been approved by the FDA, Japan, the European Union an Australia for the treatment
of severe SARs-CoV-2 infections by intravenous injection. Carboxyesterase-anhydride-HINT1 (CAH) ProTides,
such as sofosbuvir and remdesivir, utilize a four step activation process based on initial esterase hydrolysis,
carboxylic acid nucleophilic attack at the phosphorous and release of phenol, followed by mixed anhydride
chemical hydrolysis, and finally phosphoramidate hydrolysis by hHINT1. Unfortunately, although they can be
dosed intravenously, due to high first pass metabolism, CAH-Protides are limited in their use as oral drugs to
viral hepatitis. Furthermore, due to the high carboxyesterase activity of rodent plasma, it has been difficult to
carry out pre-clinical studies with rodents and translationally relevant dosages of CAH-ProTides.
 To address the inherent issues surrounding current ProTide approaches, our group has
designed an alternative ProTide approach, we refer to as anchimerically HINT1 activated proTides
(AHA-ProTides). Our laboratory has demonstrated that AHA-proTides can be designed that are stable,
orally bioavailable, cell permeable and dependent on HINT phosphoramidate hydrolysis. Recently, we
have also demonstrated that AHA proTides can be prepared with enhanced potency against DENV
and ZIKV. Consequently, we propose to the design and develop anti-DENV and anti-ZIKV AHA
ProTides that can serve as advanced lead compounds for the potential treatment of both DENV
and ZIKV disease.

## Key facts

- **NIH application ID:** 10296447
- **Project number:** 1R01AI146049-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** CARSTON R. WAGNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $670,946
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296447

## Citation

> US National Institutes of Health, RePORTER application 10296447, Anchimerically Activatable Anti-Zika/Dengue ProTides (1R01AI146049-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10296447. Licensed CC0.

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