# Development of Cell-active Giardia lamblia Methionyl-tRNA Synthetase Inhibitors as a New Therapeutic for Giardiasis

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2020 · $765,535

## Abstract

Project Summary/Abstract
Giardia lamblia is the causative agent of giardiasis, a gastrointestinal illness with symptoms including diarrhea
and malabsorption. Chronic infections can lead to long term growth retardation or death in infants, with a recent
estimate of global incidence of 280 million symptomatic cases per year. Food and Drug Administration-approved
treatments for giardiasis include metronidazole, chemically related nitroimidazole drugs, and albendazole.
However, a substantial number of clinical infections are resistant to these treatments. We have shown that
specific inhibitors of methionyl-tRNA synthetase (MetRS) prevent trophozoite growth in an engineered
bioluminescent G. lamblia strain and a metronidazole resistant G. lamblia strain. The molecular mechanism of
action seems to be the disruption of G. lamblia protein synthesis due to inhibition of GlMetRS enzyme activities.
Proof of principle compound 1717 has decent oral bioavailability and is an effective treatment in a mouse clinical
model of giardiasis, showing complete clearance of G. lamblia after 3 days. This research proposal will capitalize
on these encouraging preliminary data to develop compounds as novel anti-giardia drugs for alternative or
complementary treatment of giardiasis. We have selected 18 compounds representing 3 distinct scaffolds based
on chemical functional group diversity, GlMetRS IC50 ≤50nM, G. lamblia trophozoite EC50 ≤3000nM, and a
selectivity index of ≥ 15 defined as CC50/EC50, for toxicity in HepG2 cell cultures. Preliminary data showed that
the double-ring linker series tends to have better selectivity when compared to the other two series. We will
therefore focus on the double-ring linker compounds. Since the pharmacokinetic correlations for effective anti-
Giardia chemotherapy have not been well established, we will use these compounds to define the PK/PD
properties necessary for optimum in vivo efficacy in Aim 1. In Aim 2, we will determine: static vs. cidal properties,
rate of killing, propensity for acquired resistance and initial safety liabilities of the compounds. In Aim 3, a
combination of structure-based design, empirical SAR-driven approaches and automated quantitative
tomography of G. lamblia will be used to guide medicinal chemistry optimization of double-ring linker scaffold for
improved efficacy and PK/ADMET properties, while addressing potential safety issues. We will determine
potential toxicity and off-target effects of GlMetRS inhibitors in vitro and in rodent models. The compounds will
be tested for hERG liabilities and CYP inhibition, as well as against the mutagenesis model and a safety panel
of human receptors and ion channels. This will set the stage in Aim 4 for dose finding experiments in efficacy
models, final toxicology studies, additional resistance studies and metronidazole combination studies. The
proposed work will complete many of the steps necessary for selecting a preclinical candidate that will facilitate
innovativ...

## Key facts

- **NIH application ID:** 10241046
- **Project number:** 1R56AI146067-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kayode K Ojo
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $765,535
- **Award type:** 1
- **Project period:** 2020-09-03 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241046

## Citation

> US National Institutes of Health, RePORTER application 10241046, Development of Cell-active Giardia lamblia Methionyl-tRNA Synthetase Inhibitors as a New Therapeutic for Giardiasis (1R56AI146067-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241046. Licensed CC0.

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