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

Neglected tropical diseases caused by trypanosomatid parasites such as Leishmania, Trypanosoma brucei and Trypanosoma cruzi present a major public healthcare issue due in part to emerging resistance. Exploring multiple targeting ligands, conjugates composed of analogs from the ribosomal inhibitor anisomycin and glycosomal inhibitory almiramide peptides were made and shown to be inactive compared to the parent components. On the other hand, attachment of walkynyl chains characteristic of the lipid tails of anti-parasitic peptides to the p-position of anisomycin, gave ethers exhibiting potent activity, rivalling that of the parent ribosomal inhibitor, especially against resistant Leishmania strains. Cryo-electron microscopy revealed that the O-propargyl anisomycin analog bound similarly to the highly conserved peptidyl transferase center of the ribosome as 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. Structure-activity study has revealed the utility of alkynyl substituents for improving antiparasitic activity against resistant strains by enlarging mode of action paving the way towards novel therapy against trypanosomatid infections.