Peptide welding technology – A simple strategy for generating innovative ligands for G protein coupled receptors

Based on their high selectivity of action and low toxicity, naturally occurring peptides have great potential in terms of drug development. However, the pharmacokinetic properties of peptides, in particular their half life, are poor. Among different strategies developed for reducing susceptibility to peptidases, and thus increasing the duration of action of peptides, the generation of branched peptides has been described. However, the synthesis and purification of branched peptides are extremely complicated thus limiting their druggability. Here we present a novel and facile synthesis of tetrabranched peptides acting as GPCR ligands and their in vitro and vivo pharmacological characterization. Tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ), N/OFQ related peptides, opioid peptides, tachykinins, and neuropeptide S were generated with the strategy named peptide welding technology (PWT) and characterized by high yield and purity of the desired final product. In general, PWT derivatives displayed a pharmacological profile similar to that of the natural sequence in terms of affinity, pharmacological activity, potency, and selectivity of action in vitro. More importantly, in vivo studies demonstrated that PWT peptides are characterized by increased potency associated with long lasting duration of action. In conclusion, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.