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Publication Abstract from PubMed

Neglected tropical diseases caused by trypanosomatid parasites present a major public healthcare issue, partly due to emerging resistance. Attachment of omega-alkynyl chains characteristic of the lipid tails of antiparasitic peptides to the p-position of anisomycin gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant Leishmania strains. Single-particle cryoelectron microscopy analysis revealed that O-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 O-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.

p-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action.,Bora Bhowal K, Nguyen AMT, Ibarra-Meneses AV, Brito Lira A, Rajan KS, Castano JD, Beaudry F, Bashan A, Fernandez-Prada C, Olivier M, Yonath A, Lubell WD J Med Chem. 2025 Oct 9;68(19):20264-20282. doi: 10.1021/acs.jmedchem.5c01291. , Epub 2025 Sep 22. PMID:40980996^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.