Chemical Genetics and Molecular Pharmacology of the Oxysterol-Binding Proteins

Abstract

Oxysterol-binding protein (OSBP) and the OSBP-related proteins (ORPs) comprise a family of lipid-binding proteins organized into 6 subfamilies in humans. ORP subfamily 1 consists of OSBP and its closest homolog, ORP4. OSBP is required for the proliferation of a wide array of human pathogenic RNA viruses, while ORP4 is required for the survival and proliferation of cancer cells, making OSBP and ORP4 attractive broad-spectrum antiviral and precision anticancer targets, respectively. The overall aim of my dissertation research was to better understand the cellular biology, biochemistry, and molecular pharmacology of OSBP and ORP4. More specifically, my research uses standard cellular biology and protein biochemistry approaches, coupled with a chemical genetics approach, to probe the function, regulation, and disease contributions of OSBP and ORP4 to develop these proteins as viable drug targets; with particular emphasis on studying OSBP as a broad-spectrum antiviral target. The naturally occurring small molecule OSW-1 selectively targets OSBP and ORP4 with high affinity and is used as a chemical probe in this dissertation, along with various other small molecules, to study OSBP and ORP4. The work in this dissertation outlines the discovery and elucidation of novel OSBP cellular biology and important insights into OSBP antiviral targeting, which are critical for the development of OSBP as a clinical antiviral target. This dissertation also provides the first comprehensive structure-activity relationship (SAR) study of small-molecule ligand binding to human OSBP and ORP4 necessary to guide the development of novel small-molecule antiviral and anticancer therapeutics that target OSBP or ORP4, respectively.