Developing High-Throughput Chemical Approaches For Proteomic Profiling Of Aspartic Proteases And Protein Kinases

Abstract

To reach the goal of large scale studies of a significant number of enzymes present in any particular organism, development of high-throughput amenable chemistry and enzyme-screening tools are becoming very urgent. This thesis examines and addresses these challenges by combination of various synthetic approaches and introducing high throughput screening platforms. Chapter 2 describes a solution-cum-solid phase strategy for rapid assembly of diol-containing small molecules as potential HIV-1 inhibitors. Chapter 3 presents a high throughput synthetic strategy for rapid assembly of 475-member aspartic protease inhibitors library using ?click? reaction. With this platform, new inhibitors against malaria were discovered. Chapter 4 and 5 present a small molecule microarray-facilated platform for proteome profiling of aspartic proteases in cellular lysates. Chapter 6 and 7 describes the cell permeable, photo-affinity drug-like probes for proteome profiling of cellular on/off-targets of drug dasatinib and staurosporine.