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Chem Biol Drug Des. 2012 Feb;79(2):209-15. doi: 10.1111/j.1747-0285.2011.01261.x. Epub 2011 Nov 28.

Identification of specific tethered inhibitors for caspase-5.

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Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California at San Francisco, 1700 4th Street, San Francisco, CA 94143, USA.


The development of highly selective small molecule inhibitors for individual caspases, a class of cysteine-dependent aspartate-specific proteases, has been challenging due to conservation of the active site. Previously, we discovered an allosteric site at the dimer interface of caspases-3, -7, and -1 using disulfide trapping. Here, we show this approach can generate selective tethered ligands and inhibitors for caspase-5, which is remarkable considering its high sequence similarity to caspase-1. Among the 62 hits of a screen of ∼15 000 thiol-containing fragments, a naphthyl-thiazole-containing molecule was identified that selectively inhibited and labeled the allosteric cysteine in the p10 subunit of caspase-5, but caused very little inhibition or labeling of caspase-1. Interestingly, some of allosteric tethered compounds to caspase-5 did not inhibit its enzymatic activity, suggesting that thiol-labeling itself is not sufficient to drive inhibition. These studies validate an allosteric site on caspase-5 and provide a useful starting point to develop selective compounds to probe the role of caspase-5 separate from caspase-1 in the innate immune response.

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