Small-molecule agonists for the glucagon-like peptide 1 receptor

Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Maikun; Behrens, Carsten; Bhumralkar, Dilip; Kodra, János T.; Holst, Jens J.; Jeppesen, Claus; Johnson, Michael D.; Jong, Johannes C. de; Jorgensen, A.; Kercher, Tim; Kostrowicki, Jarek; Madsen, Peter; Olesen, Preben H.; Petersen, J.; Poulsen, F. Reibke; Sidelmann, Ulla G.; Sturis, Jeppe; Truesdale, Larry K.; May, Jeanine; Lau, Jesper

doi:10.1073/pnas.0605701104

Cited by 198 publications

(218 citation statements)

References 51 publications

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“…In addition, Boc5 and S4P largely, but not completely, displaced labeled GLP-1 from GLP-1R and may, therefore, also interact with the TMD (27). In contrast, the pyrimidine BETP (31) was not competed by exendin(9 -39) or GLP-1 and is, therefore, thought to allosterically activate GLP-1R (31)(32)(33)(34). Recent work has demonstrated that BETP functions by forming covalent adducts with Cys-347 in the intracellular loop 3 (ICL3) of GLP-1R, which may mimic a physiological covalent modification (35).…”

Section: Small Molecule Glp-1r Modulators Mimic Endogenous Peptide Homentioning

confidence: 99%

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Zhao

Yin

Yang

et al. 2016

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extracellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class B GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF 1 R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the ECD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its ECD, suggesting a direct role of the ECD in GLP-1R activation.The class B or secretin family of GPCRs consists of 15 receptors for peptide hormones that include glucagon, glucagon-like peptides, parathyroid hormone, and calcitonin (Fig. 1A). These receptors are important drug targets for many human diseases including diabetes, neurodegeneration, cardiovascular diseases, and psychiatric disorders. The full-length receptors consist of two modular domains: a globular extracellular domain (ECD) 3 defined by three conserved disulfide bonds and a TMD that contains seven transmembrane helices (1-4). The ECD is responsible for the high affinity and specificity of hormone binding, and the TMD is required for receptor activation and signal coupling to downstream G proteins and other signaling effectors (4). Peptide hormone binding is thought to proceed through fast binding of its C terminus to the ECD followed by a slower association of the peptide N terminus with the receptor TMD (5), which leads to conformational changes in the receptor TMD and the receptor activation. The activated receptors are coupled primarily to stimulatory G proteins, resulting in elevation of the intracellular cAMP level.Structures of the ECDs of class B GPCRs in complex with their peptide ligands have been determined by x-ray crystallography (1, 6 -9) and NMR (10) and have provided useful information about structural mechanisms of ligand recognition and selectivity (2, 11). Only recently, crystal structures of t...

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Section: Small Molecule Glp-1r Modulators Mimic Endogenous Peptide Homentioning

confidence: 99%

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Zhao

Yin

Yang

et al. 2016

Journal of Biological Chemistry

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“…Compound 2 significantly increases glucose-stimulated insulin release from wild-type mouse pancreatic islets and from perfused rat pancreas, although not from GLP-1 receptor knockout mouse islets. It is not particularly potent, and its oral bioavailability is not reported (2). However, these findings suggest that this class of compound may be a useful starting point for the design of further drugs based on the GLP-1 signaling system.…”

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confidence: 95%

“…The chemical compound analyzed in more detail, referred to as ''compound 2,'' not only agonizes the GLP-1 receptor, but also increases its binding affinity for GLP-1. The mechanism is unknown, although it appears that binding is allosteric, and Knudsen et al (2) suggest that it may stimulate receptor dimerization. Compound 2 significantly increases glucose-stimulated insulin release from wild-type mouse pancreatic islets and from perfused rat pancreas, although not from GLP-1 receptor knockout mouse islets.…”

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confidence: 99%

“…By synthesizing and testing further compounds, they discovered more potent GLP-1 agonists. These agonists often had bell-shaped dose-response curves, although Knudsen et al (2) report identifying similar compounds that do not inhibit intracellular cyclic adenosine monophosphate production at high concentrations. The chemical compound analyzed in more detail, referred to as ''compound 2,'' not only agonizes the GLP-1 receptor, but also increases its binding affinity for GLP-1.…”

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confidence: 99%

“…Indeed, Knudsen et al (2) found that none of the 500,000 small molecules they tested were specific agonists as assessed by competitive binding to the GLP-1 receptor. However, using a functional assay, they managed to discover that substituted quinoxalines specifically activated the GLP-1 receptor, although they did not displace GLP-1 binding from these receptors.…”

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confidence: 99%

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Nonpeptidic glucagon-like peptide 1 receptor agonists: A magic bullet for diabetes?

Murphy

Bloom

2007

Proc. Natl. Acad. Sci. U.S.A.

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Glucagon‐Like Peptide‐1 Receptor Activators

Wagner¹,

Evers²,

Bossart³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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Type 2 diabetes (T2D) and obesity have reached pandemic levels and represent a major health burden to modern society. Peptidic GLP‐1 receptor agonists (GLP‐1RAs) have been established as an effective therapy with respect to glycemic control and provide moderate body weight reduction. Marketed first‐generation GLP‐1RAs are suitable for once‐ or twice‐daily subcutaneous dosing. Their substantial benefit on glucose control led to the discovery and development of longer lasting therapeutic options to improve patient convenience and compliance. Recently reported positive cardiovascular outcome studies for some GLP‐1RAs further underscore their therapeutic value. Besides long‐lasting action, alternative delivery formats for injectable GLP‐1RAs have been explored, for example oral formulations. One such oral formulation of a GLP‐1 analog has completed Phase 3 studies and is now approved for the treatment of T2D. In contrast, the discovery of orally available small molecule agonists of the GLP‐1R has been historically challenging, and only recently a few compounds have reached early clinical development. To further improve the efficacy of GLP‐1RAs, so‐called GLP‐1R dual or triple agonists have been developed. These peptides show promising results in early clinical trials but are awaiting confirmation of their therapeutic benefit in late‐stage development.

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Small-molecule agonists for the glucagon-like peptide 1 receptor

Cited by 198 publications

References 51 publications

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

Nonpeptidic glucagon-like peptide 1 receptor agonists: A magic bullet for diabetes?

Glucagon‐Like Peptide‐1 Receptor Activators

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