Hot topic: The G Protein-Coupled Receptors deorphanization landscape.

Within the vast GPCR superfamily, orphans are described as receptors devoid of known endogenous ligands. They have been labeled as 7 transmembrane proteins by sequence homology and dispatched accordingly in the different GPCR subfamilies. They have attracted much attention given the recognized potential of GPCRs in terms of drug discovery. It is anticipated that discovering a new (and in the best case: previously unknown) ligand for an elusive receptor will open avenues in terms of innovative physiological concepts as well as unprecedented opportunities for drug discovery. However, after a couple of striking deorphanizations that confirmed their potential, the number of successful pairings between ligands and receptors has decreased.

The present paper by Laschet, Dupuis & Hanson [1] sheds some light on the current state of the field and the phenomenon of reduced discoveries in the orphan landscape. Although it is true that fewer deorphanizations have been reported recently compared to the 1990-2000 period, the authors propose that the rate has reached a “steady-state” stage. Nevertheless, with more than 100 remaining orphans, the daunting task of full deorphanization that lies ahead will require creative approaches both at the technical and conceptual level. Thus, following short historical reminders, the authors provide an extensive description of the current methods applied to deorphanization as well as emerging techniques that should help pharmacologists active in the orphan GPCR field in the near future. In addition, this review lists and discusses the deorphanizations that appeared in the literature since the last comprehensive state of the art issued by the IUPHAR (in 2013) [2] and put these pairings in their contexts, describing the probable outcomes in terms of new drug targets and previously unforeseen physiological loops.

Finally, during the collection of the recent literature about orphans, the authors noticed an important number of unconfirmed pairings and identified this as one of the major issues of the field and an important challenge for the future. Beside the deorphanized receptors that became silent after a single publication, presumably because of the failure of confirmation attempts by other teams, some ligands were openly questioned by recently published negative datasets. The paper proposes tentative explanations for inconsistencies in the literature and suggests recommendations such as critical controls that should be included when reporting a ligand for an orphan receptor.

Comments by Julien Hanson, University of Liege

  1. Laschet C, Dupuis N, Hanson J. (2018) The G Protein-Coupled Receptors deorphanization landscape. Biochem Pharmacol. pii: S0006-2952(18)30073-X. doi: 10.1016/j.bcp.2018.02.016. [Epub ahead of print] [PMID:29454621]
  2. Davenport AP, et al. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands. Pharmacol Rev. 65: 967-86. [PMID:23686350]

Note, the GtoPdb latest pairings page tracks reports of novel pairings between orphan receptors and their ligands.

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