A Multifunctional Protease Inhibitor To Regulate Endolysosomal Function

TY - JOUR

T1 - A Multifunctional Protease Inhibitor To Regulate Endolysosomal Function

AU - van Kasteren, Sander I.

AU - Berlin, Ilana

AU - Colbert, Jeff D.

AU - Keane, Doreen

AU - Ovaa, Huib

AU - Watts, Colin

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

KW - LYSOSOMAL CYSTEINE PROTEASES

KW - CATHEPSIN-D

KW - ANTIGEN PRESENTATION

KW - ASPARTIC PROTEASE

KW - PEPSTATIN

KW - RECEPTOR

KW - CYSTATINS

KW - ENDOPEPTIDASE

KW - CONJUGATE

KW - LEGUMAIN

UR - https://www.scopus.com/pages/publications/81555214610

U2 - 10.1021/cb200292c

DO - 10.1021/cb200292c

M3 - Article

C2 - 21910425

SN - 1554-8929

VL - 6

SP - 1198

EP - 1204

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 11

ER -