<i>p</i>-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action

Neglected tropical diseases caused by trypanosomatid parasites present a major public healthcare issue, partly due to emerging resistance. Attachment of ω-alkynyl chains characteristic of the lipid tails of antiparasitic peptides to the <i>p</i>-position of anisomycin gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant <i>Leishmania</i> strains. Single-particle cryoelectron microscopy analysis revealed that <i>O</i>-propargyl anisomycin binds to the highly conserved peptidyl transferase center of the ribosome similar to the parent inhibitor. Thermal proteomic profiling and gene ontology analysis demonstrated that <i>O</i>-propargyl anisomycin exhibited a broader mode of action, including activity against glycosome-associated proteins. Alkynyl substituents improved antiparasitic activity against resistant strains, likely by enlarging the mode of action, offering a novel path toward therapy against trypanosomatid infections.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-09-22
DOI
https://doi.org/10.1021/acs.jmedchem.5c01291
Primary Topic
Synthesis and Biological Evaluation
Type
article
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article

p-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action

Francis Beaudry, Martin Olivier, Christopher Fernandez‐Prada, K. Shanmugha Rajan et al.
Journal of Medicinal Chemistry
Synthesis and Biological Evaluation
article

p-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action

Francis Beaudry, Martin Olivier, Christopher Fernandez‐Prada, K. Shanmugha Rajan, Ada Yonath, A. Bashan, William D. Lubell, Andressa Brito Lira, Ana Victoria Ibarra‐Meneses, Jesús D. Castaño, Anh Minh Thao Nguyen, Kajumee Bora Bhowal
article en

Abstract

Neglected tropical diseases caused by trypanosomatid parasites present a major public healthcare issue, partly due to emerging resistance. Attachment of ω-alkynyl chains characteristic of the lipid tails of antiparasitic peptides to the <i>p</i>-position of anisomycin gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant <i>Leishmania</i> strains. Single-particle cryoelectron microscopy analysis revealed that <i>O</i>-propargyl anisomycin binds to the highly conserved peptidyl transferase center of the ribosome similar to the parent inhibitor. Thermal proteomic profiling and gene ontology analysis demonstrated that <i>O</i>-propargyl anisomycin exhibited a broader mode of action, including activity against glycosome-associated proteins. Alkynyl substituents improved antiparasitic activity against resistant strains, likely by enlarging the mode of action, offering a novel path toward therapy against trypanosomatid infections.

Journal of Medicinal ChemistryVol. 68(19)
Université du Québec à Montréal (CA), École Nationale Vétérinaire d'Alfort (FR), McGill University Health Centre (CA), Animal Production Institute (ZA), Czech Academy of Sciences, Institute of Microbiology (CZ), University of Veterinary Medicine (HU), McGill University (CA), Weizmann Institute of Science (IL), Université de Montréal (CA)
Openalex Percentile: Top 81%
Synthesis and Biological Evaluation
DOISourceOpenAlex
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