# Developmental Pharmacology of Antiretroviral Metabolism in Mucosal Tissues

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $342,560

## Abstract

Tenofovir (TFV) and other nucleotide reverse transcriptase inhibitors must be activated via phosphorylation by
intracellular nucleotide kinases in order to become pharmacologically active. While the kinases that activate TFV
in mucosal tissues in adults have been identified, studies have not been performed to determine which enzymes
phosphorylate TFV in adolescents. Further, whether hormonal changes during development might impact the
expression and activity of the kinases that have thus far been demonstrated to activate TFV hasn't been
explored. Gaining a mechanistic understanding of the expression patterns and regulation of these nucleotide
kinases across developmental stages in mucosal tissues is of particular importance within the context of using
these drugs for HIV pre-exposure prophylaxis since vaginal and colorectal tissues are putative sites of
pharmacological activity in this setting. With this in mind, the goals of this proposal are to identify the nucleotide
kinases that phosphorylate TFV in adolescent vaginal and colorectal tissue and to probe the effects of hormones
that govern developmental maturation on TFV disposition. The aims are as follows: (1) determine which kinases
activate TFV in adolescent tissue; the expression pattern of nucleotide kinases in adolescent vaginal and
colorectal tissue will be established using proteomics-based approaches; knockdown of identified kinases will
facilitate identification of those that exhibit activity toward TFV in tissue; (2) test whether TFV activation and TFV
distribution in tissue are hormonally regulated; nucleotide kinase expression will be measured in response to
developmental hormones and mechanisms of hormonal regulation will be probed; MALDI-mass spectrometry
imaging will be employed in order to visualize the distribution of TFV as well as phosphorylated metabolites of
TFV in adolescents versus adults. It is expected that the completion of the proposed studies will provide a
mechanistic foundation for the rational selection and dosing of antiretrovirals for HIV pre-exposure prophylaxis
in adolescents.

## Key facts

- **NIH application ID:** 9840866
- **Project number:** 5R01AI128781-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Namandje N Bumpus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,560
- **Award type:** 5
- **Project period:** 2017-01-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840866

## Citation

> US National Institutes of Health, RePORTER application 9840866, Developmental Pharmacology of Antiretroviral Metabolism in Mucosal Tissues (5R01AI128781-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840866. Licensed CC0.

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