title: Vinyl sulfone-based peptidomimetics as anti-trypanosomal agents: design, synthesis, biological and computational evaluation.
abstract: A series of vinyl sulfone-containing peptidomimetics were rationally designed, synthesized, and evaluated against Trypanosoma brucei brucei . These electrophilic compounds are likely to exert their antitrypanosomal activity via inhibition of trypanosomal cysteine proteases, TbCatB and rhodesain, through alkylation of a key cysteine residue within the protease active site. The series was designed to present complementary groups to naturally recognized peptide substrates while probing tolerance to a range of substitutions at the P1, P1', and P2 positions. The most potent compound, 29 (EC50 = 70 nM, T. b. brucei whole cell assay), displayed minimal toxicity (>785 times selectivity) when assayed for cytotoxicity against the human promyelocytic leukemia (HL-60) cell line. Cells treated with compound 29, as with K777 (2), exhibited an increase in both the number of multinucleated cells and cells with swollen flagellar pockets. Computational analysis revealed a strong correlation between the hypothetical binding mode in TbCatB/rhodesain and trypanocidal activity in vitro.
authors: Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin , Dublin 4, Ireland.
authors: Elizabeth
authors: E
authors: Dunny
authors: William
authors: W
authors: Doherty
authors: Paul
authors: P
authors: Evans
authors: J Paul G
authors: JP
authors: Malthouse
authors: Derek
authors: D
authors: Nolan
authors: Andrew J S
authors: AJ
authors: Knox
mesh_terms: D000818:Animals; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D057786:Peptidomimetics; D013057:Spectrum Analysis; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D057786:Peptidomimetics; D013450:Sulfones; D014344:Trypanocidal Agents; C009873:divinyl sulfone