ジャーナル: J Med Chem / 年: 2025 タイトル: -Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action. 著者: Kajumee Bora Bhowal / Anh Minh Thao Nguyen / Ana Victoria Ibarra-Meneses / Andressa Brito Lira / K Shanmugha Rajan / Jesus D Castaño / Francis Beaudry / Anat Bashan / Christopher Fernandez- ...著者: Kajumee Bora Bhowal / Anh Minh Thao Nguyen / Ana Victoria Ibarra-Meneses / Andressa Brito Lira / K Shanmugha Rajan / Jesus D Castaño / Francis Beaudry / Anat Bashan / Christopher Fernandez-Prada / Martin Olivier / Ada Yonath / William D Lubell / 要旨: 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 ...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 -position of anisomycin gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant strains. Single-particle cryoelectron microscopy analysis revealed that -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 -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.