6533b7d3fe1ef96bd126026e

RESEARCH PRODUCT

Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action

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description

Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4 nm and kinact/Ki=1.6×106 m−1 s−1 against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions. The authors thank Serveis Centrals d′Instrumentació Científica at Universitat Jaume I for technical support. S.R. thanks the Generalitat Valenciana for a postdoctoral research grant under the VALi+d Program. T.S. thanks the Deutsche Forschungsgemeinschaft (DFG) (SFB630) for financial support.