# Drug development against Entamoeba histolytica

> **NIH NIH R21** · STANFORD UNIVERSITY · 2021 · $211,597

## Abstract

ABSTRACT
Entamoeba histolytica causes dysentery and liver abscesses with invasive disease in 50 million people
annually. Despite being an important human pathogen, this organism is poorly studied, has very limited
therapeutic options, and has no significant drug development pipeline. Thus, there is a critical need for new
drugs against this pathogenic ameba. We chose a compound screening approach using the ReFRAME library,
which was generated by Calibr and the Bill and Melinda Gates Foundation to have high-value hits with the vast
majority of compounds having been tested in humans. We have completed screening of ~11,000 compounds
against E. histolytica and identified 156 primary (~1.3%) hits. We subsequently performed confirmatory testing
and confirmed 50 hits with EC50 £15µM. By considering FDA approval status, clinical trial data, hepG2 cell
toxicity and potency against E. histolytica trophozoites, we identified 19 high-priority compounds for further
testing in this grant cycle. Of these 19 priority compounds, 9 have been FDA approved or have FDA orphan
designation and an additional 7 have been in late stage human clinical trials (Phase II or III); 14 have improved
efficacy compared to metronidazole. Thus, these 19 compounds are great options for a repurposing approach.
In this R21 grant, we will characterize these high value hits in the following two aims. In Aim 1, we will test
these compounds against Entamoeba cysts (encysting cells and mature cysts), metronidazole resistant
Entamoeba, and clinical isolates. We will also determine the kinetics of parasite killing with each compound
and the delay of parasite recrudescence after drug removal. Based on these results and analysis of
pharmacokinetic data on the compounds, in Aim 2, we will select ~2-5 select compounds to test in vivo
efficacy in a mouse model of Entamoeba colitis. Successful completion of this work will identify ~2 lead
compounds/series with activity against Entamoeba histolytica. Based on our experience with amebae,
significant drug development expertise at Stanford and UCSD, and a cadre of outstanding collaborators, we
are confident of a successful outcome.

## Key facts

- **NIH application ID:** 10122895
- **Project number:** 5R21AI146651-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** UPINDER SINGH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $211,597
- **Award type:** 5
- **Project period:** 2020-03-10 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122895

## Citation

> US National Institutes of Health, RePORTER application 10122895, Drug development against Entamoeba histolytica (5R21AI146651-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10122895. Licensed CC0.

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