Identification of specific tethered inhibitors for caspase-5.

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