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Structure paper

Title-Alkoxy-Substituted Anisomycins with Potent Anti-Trypanosomiasis Activity and Expanded Modes of Action.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 19, Page 20264-20282, Year 2025
Publish dateOct 9, 2025
AuthorsKajumee 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 /
PubMed AbstractNeglected 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.
External linksJ Med Chem / PubMed:40980996
MethodsEM (single particle)
Resolution2.5 Å
Structure data

52247

9hl9

EMDB-52247, PDB-9hl9:
CRYO-EM STRUCTURE OF LEISHMANIA MAJOR 80S RIBOSOME WITH P/E-site tRNA AND mRNA : LM14Cs1H3 sKO STRAIN
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-52258: CRYO-EM CONSENSUS MAP OF LEISHMANIA MAJOR 80S RIBOSOME WITH P/E-site tRNA AND mRNA : LM14Cs1H3 sKO STRAIN
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-52259: CRYO-EM FOCUSED REFINEMENT MAP OF LEISHMANIA MAJOR 80S RIBOSOME WITH P/E-site tRNA AND mRNA : LM14Cs1H3 sKO STRAIN
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-MG:
Unknown entry

PDB-1iwa:
RUBISCO FROM GALDIERIA PARTITA

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

Source
  • leishmania major strain friedlin (eukaryote)
KeywordsRIBOSOME / CRYO-EM / LEISHMANIA MAJOR / 80S / LM14Cs1H3 / snoRNA

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