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A multifunctional protease inhibitor to regulate endolysosomal function.


ABSTRACT: Proteases constitute a major class of drug targets. Endosomal compartments harbor several protease families whose attenuation may be 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.

SUBMITTER: van Kasteren SI 

PROVIDER: S-EPMC3220280 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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A multifunctional protease inhibitor to regulate endolysosomal function.

van Kasteren Sander I SI   Berlin Ilana I   Colbert Jeff D JD   Keane Doreen D   Ovaa Huib H   Watts Colin C  

ACS chemical biology 20110919 11


Proteases constitute a major class of drug targets. Endosomal compartments harbor several protease families whose attenuation may be 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  ...[more]

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