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A multifunctional protease inhibitor to regulate endolysosomal function.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2011 Nov 18; Vol. 6 (11), pp. 1198-204. Date of Electronic Publication: 2011 Sep 19. - Publication Year :
- 2011
-
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.
- Subjects :
- Cystatins chemistry
Cysteine Proteases metabolism
Endopeptidases metabolism
Lysosomes enzymology
Lysosomes physiology
Pepstatins chemical synthesis
Pepstatins chemistry
Protease Inhibitors chemical synthesis
Protease Inhibitors chemistry
Structure-Activity Relationship
Lysosomes drug effects
Pepstatins pharmacology
Protease Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 6
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 21910425
- Full Text :
- https://doi.org/10.1021/cb200292c