Synthetic Membrane Anchored Ligands: An Innovative Approach to Drug Discovery

Abstract

Novel strategies are needed to expedite the generation and optimization of peptide probes targeting G protein‐coupled receptors (GPCRs). We have previously shown that membrane tethered ligands (MTLs), constructs comprised of a membrane anchor, an extracellular linker, and a peptide ligand, can be used to develop targeted receptor modulators. Although MTLs provide a useful tool to identify and/or modify active peptides, a major limitation of this strategy is the reliance on recombinant protein expression. We now report the generation and pharmacological characterization of prototype peptide‐linker‐lipid conjugates, synthetic membrane anchored ligands (SMALs), which are designed as mimics of corresponding recombinant MTLs. Using a range of GPCRs (NK1R, CCK2R, CMKLR1, MrgprX1, GLP‐1R), we illustrate the feasibility of the approach and highlight selected pharmacological properties of MTLs/ SMALs both in vitro and in vivo. Our results suggest that MTLs offer an expedited method to validate peptides that will have enhanced function as SMALs. Once identified and optimized as an active MTL, SMAL mimics can be generated and characterized. These synthetic constructs offer the possibility of direct administration rather than recombinant expression. Our work illustrates a two‐step approach of optimizing MTLs and then synthesizing corresponding SMALs. These membrane anchored probes provide powerful tools to investigate GPCR physiology and provides a basis for the development of novel therapeutics. Efforts are in progress to apply the MTL/ SMAL approach to the study of other cell surface proteins.