Biomimetic screening of class B G protein-coupled receptors

Devigny, Christian; Perez‐Balderas, Francisco; Hoogeland, B.; Cuboni, Serena; Webb, Katharine J; Deussing, Jan M.; Hausch, Felix

doi:10.1055/s-0031-1292463

Cited by 2 publications

(3 citation statements)

References 54 publications

(67 reference statements)

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“…Class B GPCRs are activating receptors for many endocrine peptide hormones (32,33), including glucosedependent insulinotropic polypeptide, glucagon, parathyroid hormone, vasoactive intestinal peptide, secretin, corticotropin-releasing factor, calcitonin, and GLP-1. The endogenous ligands of class B GPCRs are typically 30-40 amino acids in size, which limits their clinical applications owing to poor stability and the requirement of injections (32), like GLP-1 peptide.…”

Section: Discussionmentioning

confidence: 99%

“…The endogenous ligands of class B GPCRs are typically 30-40 amino acids in size, which limits their clinical applications owing to poor stability and the requirement of injections (32), like GLP-1 peptide. Unfortunately, traditional small-chemical molecules minimally modulate the activities of class B GPCRs because of the unique structural architectures and activation mechanisms used by these GPCRs (33). Although many efforts have been made to screen smallclass B GPCR agonists, much difficulty has been encountered in identifying small organic molecules by class B GPCRs.…”

Section: Discussionmentioning

confidence: 99%

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Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

Liu

Zheng

et al. 2017

FASEB j.

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The physiologic properties of glucagon-like peptide 1 (GLP-1) make it a potent candidate drug target in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 is capable of regulating the blood glucose level by insulin secretion after administration of oral glucose. The advantages of GLP-1 for the avoidance of hypoglycemia and the control of body weight are attractive despite its poor stability. The clinical efficacies of long-acting GLP-1 derivatives strongly support discovery pursuits aimed at identifying and developing orally active, small-molecule GLP-1 receptor (GLP-1R) agonists. The purpose of this study was to identify and characterize a novel oral agonist of GLP-1R (i.e., myricetin). The insulinotropic characterization of myricetin was performed in isolated islets and in Wistar rats. Long-term oral administration of myricetin demonstrated glucoregulatory activity. The data in this study suggest that myricetin might be a potential drug candidate for the treatment of T2DM as a GLP-1R agonist. Further structural modifications on myricetin might improve its pharmacology and pharmacokinetics.—Li, Y., Zheng, X., Yi, X., Liu, C., Kong, D., Zhang, J., Gong, M. Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

Liu

Zheng

et al. 2017

FASEB j.

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“…The mechanism by which the endogenous ligands for family B GPCRs, like CGRP, bind to and activate their receptors is of considerable interest (Neumann et al, 2008;Parthier et al, 2009;Watkins et al, 2012) because this can lead to the design of novel antagonists and agonists. Understanding the structure-activity relationships of natural peptides has led to the development of several stable and efficacious peptide-based agonists of family B GPCRs that have ultimately become therapeutics (Shimizu et al, 2000;Devigny et al, 2011;Garber, 2012). This review considers recent developments in the structure-activity relationship for CGRP and how these might be interpreted in the light of current knowledge of the binding of ligands to family B GPCRs.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships for α‐calcitonin gene‐related peptide

Watkins

Rathbone

Barwell

et al. 2013

British J Pharmacology

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Calcitonin gene-related peptide (CGRP) is a member of the calcitonin (CT) family of peptides. It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. With other members of the CT family, it shares an N-terminal disulphide-bonded ring which is essential for biological activity, an area of potential a-helix, and a C-terminal amide. CGRP binds to the calcitonin receptor-like receptor (CLR) in complex with receptor activity-modifying protein 1 (RAMP1), a member of the family B (or secretin-like) GPCRs. It can also activate other CLR or calcitonin-receptor/RAMP complexes. This 37 amino acid peptide comprises the N-terminal ring that is required for receptor activation (residues 1-7); an a-helix (residues 8-18), a region incorporating a b-bend (residues 19-26) and the C-terminal portion (residues 27-37), that is characterized by bends between residues 28-30 and 33-34. A few residues have been identified that seem to make major contributions to receptor binding and activation, with a larger number contributing either to minor interactions (which collectively may be significant), or to maintaining the conformation of the bound peptide. It is not clear if CGRP follows the pattern of other family B GPCRs in binding largely as an a-helix. LINKED ARTICLESThis article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx

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Biomimetic screening of class B G protein-coupled receptors

Cited by 2 publications

References 54 publications

Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

Structure–activity relationships for α‐calcitonin gene‐related peptide

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