IID432, a parasite-selective topoisomerase II inhibitor, achieves rapid single-dose parasite clearance in a murine chronic Chagas model
Chagas disease is a neglected disease that affects millions of people from the Latin American region. Current nitroheterocyclic therapies suffer from long treatment duration and safety-related treatment discontinuations. A safe, short course therapy would significantly benefit Chagas patients. Here, we report the comprehensive biological, structural, pharmacodynamic, and pharmacokinetic characterization of IID432, an optimized cyanotriazole with superior potency, favorable pharmacokinetics, and improved safety profile compared to the lead compound CT1. IID432 is a fast-acting, parasite-selective topoisomerase II poison that achieves sterile cure after a single oral dose in a murine model of chronic Trypanosoma cruzi infection. Mechanistically, IID432 stabilizes the parasite TcTopoII-DNA cleavage complex by covalently engaging a parasite-specific cysteine (Cys477), thereby conferring selectivity over the human TOP2A. IID432 displays favorable oral pharmacokinetics, with no off-target activity on human topoisomerases. Brief exposure of IID432 rapidly induces parasite-specific DNA damage and produces sterilizing activity in vitro and in vivo without recrudescence. Together, these findings identify IID432 as a first-in-class, parasite-selective covalent topoisomerase poison with a potential to significantly shorten treatment duration for T. cruzi infections.
Authors
- Catherine A. Luu (ORCID: https://orcid.org/0009-0005-1738-5319)
- Olivier René (ORCID: https://orcid.org/0009-0007-2239-4003)
- Ujjini H. Manjunatha (ORCID: https://orcid.org/0000-0002-7461-9303)
- Johanne Blais (ORCID: https://orcid.org/0000-0001-8139-8855)
- Manuel Saldivia (ORCID: https://orcid.org/0000-0001-6204-0460)
- Amanda Fortes Francisco (ORCID: https://orcid.org/0000-0002-3475-8130)
- Debjani Patra (ORCID: https://orcid.org/0000-0003-4343-4645)
- J. Noeske (ORCID: https://orcid.org/0000-0002-8750-2008)
- Srinivasa P. S. Rao (ORCID: https://orcid.org/0000-0002-7156-5725)
- Yen‐Liang Chen (ORCID: https://orcid.org/0000-0002-0121-5658)
- Jean-René Galarneau
- Domenico Bullara
- John M. Kelly (ORCID: https://orcid.org/0000-0003-4305-5258)
- Andreas D. Schenk (ORCID: https://orcid.org/0000-0001-9214-2505)
- Rajiv S. Jumani (ORCID: https://orcid.org/0000-0003-1360-6004)
- Colin Osborne (ORCID: https://orcid.org/0000-0002-5777-5427)
- Dennis C. Koester (ORCID: https://orcid.org/0000-0003-2236-6372)
- Bryanna Thomas (ORCID: https://orcid.org/0009-0001-4809-3969)
- Jonathan E. Gable
- Grace M. Baxley
- Scott A. Hollingsworth (1461244)
- Colin Deniston
- Harry Cheung
- Christopher Sarko
- Charles Wartchow
- Natasha Hochberg
- Jan Jiricek
- Thierry T. Diagana
- Jayant Sancheti
- Suresh B. Lakshminarayana
- Samarth Thakore
- Charlie G. Knutson
- Reginara Souza DeAsis
Institutions
- Novartis (Switzerland) (CH)
- London School of Hygiene & Tropical Medicine (GB)
- Novartis (India) (IN)
- Novartis (China) (CN)
- Protein Express (United States) (US)
- Health Biomed (China) (CN)
- System Simulation (United Kingdom) (GB)
- Molecular Discovery (United Kingdom) (GB)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-09-09
- DOI
- https://doi.org/10.1073/pnas.2620085123
- Primary Topic
- Trypanosoma species research and implications
- Type
- article
- Field-Weighted Citation Impact
- 0.00