A Multifunctional Protease Inhibitor To Regulate Endolysosomal Function

作者：van Kasteren Sander I^*; Berlin Ilana; Colbert Jeff D; Keane Doreen; Ovaa Huib; Watts Colin

来源：ACS Chemical Biology, 2011, 6(11): 1198-1204.

DOI：10.1021/cb200292c

Proteases constitute a major class of drug targets. Endosomal, compartments harbor several protease families whose attenuation maybe beneficial to a number of biological processes, including inflammation, cancer metastasis, antigen presentation,. and parasite clearance. As a step toward the goal of generalized but targeted protease inhibition in the endocytic pathway, we describe here the synthesis, characterization, and cellular application of a novel multifunctional protease inhibitor. We show that pepstatin A, a potent but virtually insoluble inhibitor of cathepsins D and E, can be conjugated to a single site on cystatin C, a potent inhibitor of the papain-like cysteine proteases (PLCP) and of asparagine endopeptidease (AEP), to create a highly soluble compound capable of suppressing the activity of all 3 principal protease families found in endosomes and lysosomes. We demonstrate that this cystatin-pepstatin inhibitor (CPI) can be taken up by cells to modulate protease activity and affect biological responses.

• 出版日期2011-11