# Exploring T. cruzi IMPDH as a promising target through Chagas Box screening and AVN-944 inhibition

## TL;DR

Researchers explore T. cruzi IMPDH as a new drug target for Chagas disease and find AVN-944 to be a promising treatment candidate.

## Contribution

The study identifies TcIMPDH as a druggable target and demonstrates AVN-944's efficacy against Chagas disease in cell-based assays.

## Key findings

- AVN-944 inhibits TcIMPDH with submicromolar IC50 and outperforms benznidazole in infected cardiomyoblasts.
- TcIMPDH shows conserved catalytic and allosteric residues, supporting its druggability.
- TCMDC-143376 is identified as structurally similar to clinical IMPDH inhibitors.

## Abstract

Chagas disease, caused by Trypanosoma cruzi, remains a leading cause of heart failure in Latin America, with current treatments limited to acute-phase efficacy, significant toxicity, and emerging resistance. Inosine monophosphate dehydrogenase (IMPDH) is an essential enzyme in guanine nucleotide salvage pathway and represents a promising alternative target. Here, we combined computational screening, biochemical and cell-based phenotypic assays that support T. cruzi IMPDH (TcIMPDH) as a druggable target and identify repurposing opportunities among clinical-stage inhibitors. Using Tanimoto similarity scoring against the library of 222 Chagas Box compounds, we identified TCMDC-143376 as uniquely similar to the clinical IMPDH inhibitors merimepodib and AVN-944. Phylogenetic analysis and multiple sequence alignment confirmed conservation of both catalytic and allosteric residues—drawn from T. foetus and T. brucei structures—within TcIMPDH. Recombinant TcIMPDH kinetics revealed Michaelis constants of 155 µM for IMP and 292 µM for NAD+. Biochemical IC50 assays showed submicromolar inhibition by AVN-944 (0.20 µM), (S)-Merimepodib (0.21 µM), and (R)-Merimepodib (0.37 µM). In H9c2 cardiomyoblasts infected with intracellular amastigotes, AVN-944 achieved the lowest EC50 (0.4 µM), outperforming benznidazole (EC50 = 3.0 µM) and other inhibitors. Our findings support TcIMPDH as a promising alternative drug target for Chagas disease and position AVN-944 as a compelling candidate to evaluate this therapeutic strategy in animal models.