Identification of adipokine receptor agonists and turning them to antagonists

Receptor-ligand interactions represent one of the most basic processes in biological systems. Receptor activation and deactivation induce or prevent a series of downstream signaling events that ultimately result in normal or abnormal cellular functions. Contemporary biology is in continuous search for the identification of novel receptors and their ligands. The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including leptin and adiponectin. A recent discovery and design process for leptin and adiponectin receptor response modifier peptides can be generalized to a series of transmembrane receptor ligands. A family of 11-13 amino acid residue-long leptin receptor (ObR) agonists has been identified by analyzing the effect of peptides corresponding to the three presumed active sites of leptin on the growth of leptin-responsive cancer cells. In the case of adiponectin, overlapping peptides were walked across the entire globular domain of the protein to identify the active site and derive adiponectin receptor (AdipoR) agonist peptides. In both sets, native residues were replaced by nonnatural analogs to improve the pharmacological properties including stability, efficacy and targeting. Later the ObR analogs were converted into true ObR antagonists that show antagonist-agonist selectivity of 1,000 in cellular assays. The design process of ObR antagonists included shortening of the peptide length and incorporating additional nonnatural residues. Here I take a look into this receptor agonist and antagonist discovery process from a practical point of view.