# Malaria Topoisomerase inhibitors

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $490,036

## Abstract

   
DESCRIPTION (provided by applicant): Yearly, malaria kills 0.5 million people and infects over 300 million individuals. Few enzymes are unambiguous targets of approved antimalarials, so new high-value metabolic targets and their inhibitors are needed. Many clinically approved antibacterial and anticancer agents target DNA topoisomerases. While the community has lacked pure and stable malarial topoisomerases to work with, there are intriguing hints from preliminary data that clinically-approved antimalarials, such as pyronaridine, may inhibit malaria topoisomerases. A three-year NIH-funded research program has allowed our team to express large quantities of stable malaria topoisomerases, to setup robust assays for Plasmodium falciparum topoisomerase II and related enzymes, and to obtain the first x-ray crystal structure of a malarial topoisomerase II. With these resources, in Aim 1, we will start a thorough exploration of cell-active antimalarials to identify front-runner PfTopoII inhibitors for optimizaton. In Aims 2 and 3, iterative medicinal chemistry will be guided by inhibition of enzyme and cell proliferation, target validation, PK-PD studies, safety evaluations, and activity against different
stages of the parasite life-cycle, all to help deliver an antimalarial preclinical candidate. Based
on our previous experiences, learnings, and success with malarial dihydroorotate dehydrogenase (DHODH) inhibitors, we are confident in our ability to develop antimalarials directed at P. falciparum and P. vivax topoisomerases that have clinical potential.

## Key facts

- **NIH application ID:** 9838136
- **Project number:** 5R01AI093380-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** PRADIPSINH K. RATHOD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,036
- **Award type:** 5
- **Project period:** 2011-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838136

## Citation

> US National Institutes of Health, RePORTER application 9838136, Malaria Topoisomerase inhibitors (5R01AI093380-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9838136. Licensed CC0.

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