Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 3, Pages 211-216Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00474
Keywords
Copper-catalyzed azide-alkyne cycloaddition; cysteine proteases; human cathepsin B; nitrile inhibitors
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Funding
- Gender Equality Center of the Bonn-Rhein-Sieg University of Applied Sciences
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An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited K-i values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.
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