# Targeting trypanosomatid deoxyhypusine synthase

> **NIH NIH R33** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $459,000

## Abstract

Project Description.
Trypanosomatid parasites are the causative agents of human African trypanosomiasis (HAT),
Leishmaniasis and Chagas disease, all of which are listed by the WHO as Neglected tropical diseases
(NTDs). Collectively 18-20 million people are infected with one of these parasites, yet drug therapies
remain inadequate for all three diseases. Discovery of a drug-target that could be exploited against all
three parasites, while not showing toxicity against the host, would provide a robust new approach to
combat these diseases. Eukaryotes universally require a translation factor called eIF5A for cell growth.
To be active eIF5A must be post-translationally modified on a conserved lysine reside to generate a
novel amino acid called hypusine. The hypusine modification of eIF5A is catalyzed by deoxyhypusine
synthase (DHS) using spermidine as a substrate. DHS is an essential enzyme in all eukaryotes including
the trypanosomatids. We previously demonstrated that DHS from trypanosomatids and Entamoeba have
uniquely evolved to require heterotetramer formation between two paralogous gene products to generate
the active enzyme. This unusual configuration of these parasite DHSs suggests that it may be feasible to
identify selective inhibitors of the parasite enzymes that don't inhibit human DHS. The goal of this
proposal is to determine if drug-like inhibitors of DHS that are selective for the trypanosomatid enzymes
can be identified and if so to advance them during a lead optimization program for the treatment of HAT.
In the R21 phase of this proposal we plan to develop a high throughput screen (HTS) compatible assay
for T. brucei DHS and to use this assay to screen the UT Southwestern 200,000 compound library for T.
brucei DHS inhibitors. We will perform hit validation on identified inhibitors and determine if the
identified inhibitors show good selectivity versus human DHS. If trypanosomatid specific DHS
inhibitors with good drug like properties can be identified than in the R33 phase of the proposal we plan
a hit to lead optimization of at least one series with appropriate properties to be advanced for the
treatment of HAT. Identified DHS inhibitors will also be tested at various stages during hit validation
and lead optimization against T. cruzi and Leishmania to determine if they have the potential to be
developed as a broad-spectrum treatment for all three trypanosomatid-based diseases.

## Key facts

- **NIH application ID:** 9832170
- **Project number:** 5R33AI127503-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Margaret A. Phillips
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,000
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832170

## Citation

> US National Institutes of Health, RePORTER application 9832170, Targeting trypanosomatid deoxyhypusine synthase (5R33AI127503-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9832170. Licensed CC0.

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