Date of Degree

10-2014

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

SANJAI KUMAR

Maria Tamargo

Subject Categories

Biochemistry | Chemistry | Organic Chemistry

Abstract

Cysteine cathepsins are an important class of enzymes that coordinate a variety of important cellular processes, and are implicated in various types of human diseases. Still however, many of their cellular function remain poorly understood. Chemical biology approaches employing small molecules can be utilized for this purpose. Unfortunately small molecule probes that are cell-permeable and non-peptidyl in nature are scarcely available.

In this work, first a library of sulfonyloxiranes is synthesized. From this library, 2-(2-ethylphenylsulfonyl)oxirane is identified as a selective inhibitor of cysteine cathepsins. Cell-based study reveals that 2-(2-ethylphenylsulfonyl)oxirane is a cell-permeable, covalent, and irreversible inhibitor of cathepsin B with modest efficacy.

Next, a hybrid-design approach is undertaken to develop a highly potent and selective peptidyl vinylsulfonates inhibitor (KD-1) of human cathepsin L. Studies involving human breast carcinoma MDA-MB-231 cells establishes that this inhibitor can successfully block intracellular cathepsin L activity, and retards the cell-migratory potential of these highly metastatic cells. This work has been further extended to develop an activity-based probe (KDP-1) of cathepsin L by suitable modification of KD-1 inhibitory scaffold. KDP-1 has been found to be so far the most potent activity-based probe of cathepsin L. Cell-based studies are currently underway to demonstrate the cellular efficacy of KDP-1. Further, KDP-1 is anticipated to find extensive applications in proteome-wide analysis of cathepsin L activity in both normal and diseased cells.

 
 

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