Modified Phosphatidylinositols for the investigation of peptide assemblies

Abstract

Phosphatidylinositolphosphates (PIPs) are phospholipids composed of a polar inositol headgroup connected to a diacylglycerol (DAG) via a phosphate ester. Playing a crucial role in signal transduction pathways, PIPs mainly serve the purpose of enabling Ca2+-flux from the endoplasmatic reticulum through enzymatic liberation of inositoltriphosphate (IP3). In recent years, it was found that PIPs are also a critical factor for the stabilization of the serotonin transporter´s (SERT) oligomeric structure, determined via mutational studies and single molecule light microscopy. To enable a comprehensive investigation of the interactions between PIP and SERT, highly stable and fluorescent analogs of PIP are needed. Therefore, the presented work deals with the synthesis of such analogues, spanning from simple model compounds to structurally and functionally more complex and diverse members of the PI-family. By modifying the PIP-framework, we aim to create more stable, photo-linkable, and fluorescent compounds. This involves the introduction of handles such as azides and alkynes for "click-chemistry" conjugation to fluorophores, as well as carbene donors like diazirines for irreversible photo-linking to SERT at the site of the DAG.