# Methionyl-tRNA Synthetase inhibitors can be developed as novel Giardiasis therapeutics

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $467,420

## 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. However, a substantial number of clinical
infections are resistant to currently available treatments, especially metronidazole. We have shown that specific
inhibitors of methionyl-tRNA synthetase (MetRS) representing 3 scaffolds in an available ~600 library prevent
growth in wild-type and metronidazole resistant G. lamblia strains. 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 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. Also, in Aim 1, we will determine structural activity relationships
and select compounds with high potency against GlMetRS and multiple G. lamblia strains. In Aim 2, we will
determine: static vs. cidal properties, rate of killing, propensity for acquired resistance and initial safety liabilities
of the compounds. A combination of structure-based design, empirical SAR-driven approaches and automated
quantitative tomography of G. lamblia will be used in Aim 3 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 preclin...

## Key facts

- **NIH application ID:** 10180723
- **Project number:** 1R01AI158524-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kayode K Ojo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $467,420
- **Award type:** 1
- **Project period:** 2021-04-14 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180723

## Citation

> US National Institutes of Health, RePORTER application 10180723, Methionyl-tRNA Synthetase inhibitors can be developed as novel Giardiasis therapeutics (1R01AI158524-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10180723. Licensed CC0.

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