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Dipeptidyl enoates as potent rhodesain inhibitors that display a dual mode of action

Royo, Santiago and Rodríguez, Santiago and Schirmeister, Tanja and Kesselring, Jochen and Kaiser, Marcel and González, Florenci V.. (2015) Dipeptidyl enoates as potent rhodesain inhibitors that display a dual mode of action. ChemMedChem, 10 (9). pp. 1484-1487.

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Official URL: http://edoc.unibas.ch/42081/

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Abstract

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 =1.6×10(6) 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1860-7179
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:30 Jun 2016 11:03
Deposited On:21 Apr 2016 11:45

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