# Targeting a New Therapy for Trypanosomatids

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $663,007

## Abstract

PROJECT SUMMARY: One billion people in the developing world are at risk for leishmaniasis, which
disfigures or kills nearly 2 million people each year. Current therapies for leishmaniasis and the related
parasitic diseases human African trypanosomiasis and Chagas disease are poorly effective and toxic. No
drugs that can treat all three of these infectious diseases are available. Our long-term goal is to develop an
effective new drug for trypanosomatid infections. By screening a small molecule compound collection against
Leishmania amazonensis, we have identified a new scaffold with potent and selective anti-trypanosomatid
activity. Our most potent analog has an EC50 of 15 nM against L. amazonensis axenic amastigotes (50 nM for
intracellular amastigotes) and a selectivity index of 49. Our chemical series has a broad efficacy range, and
several analogs have potency, selectivity, solubility, and stability indices over published advancement criteria.
Our data suggest that these compounds facilitate tubulin polymerization, which would be a novel mechanism of
action for antiprotozoal drugs. The objective of these studies is to identify a late lead compound with the
potential to advance for the treatment of cutaneous leishmaniasis. In Aim 1, we will define the molecular target
of our compound. We will use genetic and chemical biology approaches to characterize its interaction with
tubulin and identify relevant binding partners. In Aim 2, we will identify antileishmanial compounds with in vitro
and in vivo efficacy. Compounds will progress from validated hits to early leads and then late leads if they meet
published criteria. We will improve efficacy and chemical properties using an iterative medicinal chemistry
approach in which the synthesis strategy is informed by a cascade that includes testing for in vitro potency
against parasites and tubulin, assessing selectivity with cytotoxicity assays, and characterizing ADME
properties (e.g., metabolic stability, aqueous solubility and plasma stability) and pharmacokinetics (PK). To
progress to early leads, compounds must demonstrate efficacy in a proof-of-concept mouse model for
cutaneous leishmaniasis. To progress to late leads, compounds must cure lesions in mice caused by a panel
of cutaneous Leishmania species. Our most promising leads will undergo safety pharmacology studies (e.g.,
CYP inhibition, Ames testing, and CEREP panels). We will also determine the product profile of our leads for
future development and human administration. In Aim 3, we will obtain backup scaffolds by screening for
antileishmanial agents that affect tubulin dynamics. We will determine hit selectivity for parasite rather than
mammalian tubulin and test the most potent and selective tubulin effectors for activity against L. amazonensis.
Upon Aim completion, we will have identified a late lead compound for cutaneous leishmaniasis and additional
backup candidates for further evaluation. Our research is significant and innovative be...

## Key facts

- **NIH application ID:** 9952319
- **Project number:** 5R01AI146349-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Dawn Marie Wetzel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,007
- **Award type:** 5
- **Project period:** 2019-06-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952319

## Citation

> US National Institutes of Health, RePORTER application 9952319, Targeting a New Therapy for Trypanosomatids (5R01AI146349-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9952319. Licensed CC0.

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