Design and Synthesis of Metabolically Stabilized Lipid Probes for the Investigation of Protein–Lipid Binding Interactions

Protein–lipid binding interactions play crucial roles in various physiological and pathological processes, making it very important to study these interactions at the molecular level. However, investigation of these interactions is complicated by several issues, including the inherent complexity of membranes as well as the diverse mechanisms by which proteins interact with the membrane surfaces. As a result, many of these interactions remain poorly characterized. Synthetic probes are useful tools employed for studying protein–lipid binding interactions. This thesis will detail the design and synthesis of metabolically stabilized analogues of various signaling lipids, which mimic the natural species and are not easily modified by enzymes present in biological systems. A modular approach is employed for synthesizing these lipid probes, giving access to a wide range of derivatized lipid probes that can then be used for several studies. Although a wide variety of metabolically stabilized lipid analogues have been synthesized, their activity has not yet been characterized and quantified in detail. So, there is a great need to synthesize biologically active phosphorothioate and phosphonate analogues of various signaling lipids in order to properly characterize and compare the binding affinities and activity of these analogues. Synthesis of metabolically stabilized lipid analogue would take us one step closer towards understanding protein–lipid interactions in biological systems and in trying to find answers to the myriad of questions pertaining to these systems.