Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

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Design, synthesis and biological evaluation of PEGylated Xenopus glucagon-like peptide-1 derivatives as long-acting hypoglycemic agents

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2017.03.032 ◽

2017 ◽

Vol 132 ◽

pp. 81-89 ◽

Cited By ~ 21

Author(s):

Jing Han ◽

Yiyun Wang ◽

Qinghua Meng ◽

Guangchao Li ◽

Fangmin Huang ◽

...

Keyword(s):

Biological Evaluation ◽

Hypoglycemic Agents ◽

Design Synthesis ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting ◽

Synthesis And Biological Evaluation

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Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

Nature Communications ◽

10.1038/s41467-021-24058-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zhaotong Cong ◽

Li-Nan Chen ◽

Honglei Ma ◽

Qingtong Zhou ◽

Xinyu Zou ◽

...

Keyword(s):

Drug Target ◽

Metabolic Disorders ◽

Allosteric Modulation ◽

Structural Basis ◽

Allosteric Modulators ◽

Cryo Electron Microscopy ◽

Covalently Bonded ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Orthosteric Ligands

AbstractThe glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.

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Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.128342 ◽

2021 ◽

Vol 50 ◽

pp. 128342

Author(s):

Yousuke Yamada ◽

Kristen Gilliland ◽

Zixiu Xiang ◽

Daniel Haymer ◽

Katherine E. Crocker ◽

...

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Ex Vivo ◽

Allosteric Modulators ◽

Design Synthesis ◽

Metabotropic Glutamate ◽

Positive Allosteric Modulators ◽

Group Ii

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Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

Experimental Diabetes Research ◽

10.1155/2012/470851 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 36

Author(s):

Francis S. Willard ◽

Kyle W. Sloop

Keyword(s):

Molecular Mechanisms ◽

Three Dimensional ◽

Receptor Occupancy ◽

Allosteric Modulators ◽

Three Dimensional Modeling ◽

Dimensional Modeling ◽

Signaling Mechanisms ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

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