Discovery of Novel Regulatory Peptides by Reverse Pharmacology: Spotlight on Chemerin and the RF-amide Peptides Metastin and QRFP

Abstract

Reverse pharmacology is a screening technology that matches G protein-coupled receptors (GPCRs) with unknown cognate ligands in cell-based screening assays by detection of agonist-induced signaling pathways. One decade spent pursuing orphan GPCR screening by this technique assigned over 30 ligand/receptor pairs and revealed previously known or novel undescribed ligands, mostly of a peptidic nature. In this review, we describe the discovery, characterization of the structural composition, biological function, physiological role and therapeutic potential of three recently identified peptidic ligands. These are metastin, QRFP in a context of five RF-amide genes described in humans and the chemoattractant, chemerin. Metastin was initially characterized as a metastasis inhibitor. Investigations using ligand/receptor pairing revealed that metastin was involved in a variety of physiological processes, including endocrine function during pregnancy and gonad development. The novel RF-amide QRFP is implicated in food intake and aldosterone release from the adrenal cortex in the rat. Chemerin, first described as TIG2, is upregulated in tazarotene-treated psoriatic skin. By GPCR screening, bioactive chemerin was isolated from ovarial carcinoma fluid as well as hemofiltrate. Characterization as a chemoattractant for immature dendritic cells and analysis of the expression profile of metastin and its receptor suggested a physiological role of chemerin as a mediator of the immune response, inflammatory processes and bone development.

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

“…Metastin, the peptide product of the KISS1 gene, was identified as the endogenous ligand for GPR54 by three independent groups (Kotani et al, 2001;Muir et al, 2001;Ohtaki et al, 2001). This peptide ligand was initially termed metastin after its ability to inhibit metastasis and was classified as a member of the Arg-Phe (RF)-amide family, a group that also includes PrRP, QRFP, and NPFF (Kutzleb et al, 2005). The KISS1 gene was named for its place of discovery, Hershey, Pennsylvania, home of the "Hershey's Kisses" sweets.…”

Discovery and Validation of Novel Peptide Agonists for G-protein-coupled Receptors

“…Lately, a major effort was made by many academic institutes as well as biotech and pharmaceutical companies to identify both natural and surrogate ligands for both known and orphan GPCRs (5,6). The most common method to screen for novel GPCR activators is through large scale screening of hundreds and thousands of compounds on many GPCRs, testing for in vitro activation of any given receptor by assessing its signaling response of an expressing cell to binding of a specific compound or tissue extract.…”

Epithelial cells in fetal intestine produce chemerin to recruit macrophages

“…Chemerin (previously known as tazarotene-induced gene-2/ TIG2 or retinoic acid receptor responder-2/RARRES2) is a recently discovered chemoattractant with potent activity for macrophages and dendritic cells, which express the cell surface cognate receptor CMKLR1 (chemokine-like receptor-1, previously ChemR23), but not for neutrophils or lymphocytes (27,63). In this study, we investigated the role of chemerin as a macrophage chemoattractant in the fetal intestine.…”