Synthesis of Trifunctional Phosphatidylserine Probes for Identification of Lipid-Binding Proteins

Phosphatidylserine ( PS) lipids play a number of roles in cell biology, one of which is to mark apoptotic cells for clearance by macrophages. PS recognition triggers macrophage recognition and clearance, which occurs concomitantly with active suppression of an inflammatory response. A small number of proteins in different tissues have been identified as PS receptors, and we hypothesize that many more PS receptors have yet to be found. We have designed and synthesized a set of phosphatidylserine lipid mimics with a PS lipid headgroup for recognition, a benzophenone moiety for photoaffinity cross-linking, and an alkyne for post-labeling readout. These probes may be useful tools to identify new PS receptors (PSRs). The PS lipid probes thus have potential impact in the areas of discovery biology, anti-inflammatory therapeutics, and cellular delivery. We present herein a versatile and robust synthetic approach to trifunctional phosphatidyl serine lipid mimics for identification of novel PSR proteins.