The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent

Furman, Brian L.

doi:10.1016/j.toxicon.2010.12.016

Cited by 134 publications

(93 citation statements)

References 103 publications

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“…Exenatide exhibits approximately 50% amino acid identity with human GLP-1 and has an affinity for the GLP-1R that is equivalent to native GLP-1. It contains a glycine residue at position 2, which provides resistance to degradation by DPP-IV and an increased circulating half-life (Furman 2012). Exenatide is the most widely studied of the GLP-1R agonists, with over 7 years of continuous clinical follow-up data.…”

Section: Glp-1r Agonistsmentioning

confidence: 99%

Targeting the gastrointestinal tract to treat type 2 diabetes

Bauer

Duca

2016

Journal of Endocrinology

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The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise.

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Section: Glp-1r Agonistsmentioning

confidence: 99%

Targeting the gastrointestinal tract to treat type 2 diabetes

Bauer

Duca

2016

Journal of Endocrinology

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“…The family B GPCR, 3 GLP-1R, is an important target for the treatment of type II diabetes mellitus, and it has multiple endogenous ligands, including four forms of GLP-1, plus the related peptide oxyntomodulin (1,2). Therapeutically, the mimetic peptide exendin-4 and metabolically stabilized forms of GLP-1 have recently been approved for treatment of type II diabetes mellitus (3,4), although an oxyntomodulin derivative is also in clinical trials.…”

mentioning

confidence: 99%

“…Therapeutically, the mimetic peptide exendin-4 and metabolically stabilized forms of GLP-1 have recently been approved for treatment of type II diabetes mellitus (3,4), although an oxyntomodulin derivative is also in clinical trials. In addition, there are a number of small molecule agonists/modulators that can augment responses via the GLP-1R (5)(6)(7)(8), including the Novo Nordisk compound 2 (6).…”

mentioning

confidence: 99%

Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Differentially Regulates Orthosteric but Not Allosteric Agonist Binding and Function

Koole

Wootten

Simms

et al. 2012

Journal of Biological Chemistry

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Background:The ECL2 of the GLP-1R is critical for GLP-1 peptide-mediated selective signaling. Results: Mutation of most ECL2 residues to alanine results in changes in binding and/or efficacy of oxyntomodulin and exendin-4 but not allosteric agonists. Conclusion: ECL2 of the GLP-1R has ligand-specific as well as general effects on peptide agonist-mediated receptor activation. Significance: This work provides insight into control of family B GPCR activation transition.

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“…These toxins have been isolated mainly from cone snails venoms such as conopressin interacting with vasopressin receptor 7 , contulakin-G which binds to neurotensin receptor 8 , ρ-conotoxin TIA specific of the α 1A -adrenoceptor 9 and the τ-conotoxin CnVA that interacts with the somatostatin sst3 receptor 10 . The black widow spider and the gila monster provide further examples of GPCRs interacting toxins, namely, α-latrotoxin interacting with the latrophilin receptor 11 and exenatide, exploited as an anti-diabetic drug 12 , that targets the GLP-1 receptor, respectively. In addition, mamba venoms contain aminergic toxins that recognize various bioaminergic receptors [13][14][15][16][17][18][19] .…”

mentioning

confidence: 99%

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Blanchet

Stura

Mourier

et al. 2018

Toxicon

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Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most α 1A -adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three α2 adrenoceptor subtypes. Three positions in the ρ-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the α 1 and α 2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.Evolutionary processes of venomous animals have selected enzymes and disulfide-rich peptides in their venoms to improve their ability to subdue their prey and defend against predators. These compounds act predominantly on few, well characterized and physiologically-relevant molecular targets of the envenomed animals 1 . Recruited by convergent evolution, toxins impact mainly the haemostatic, nervous and cardiovascular systems 2 . Some toxins present in venoms, in spite of their debilitating effects, have become live-saving drugs [3][4][5] . To exert their biological activities, toxins interact mainly with ion channels, coagulation factors, nicotinic receptors, cell membrane or enzymes but only rarely with the most important class of physiological targets, i.e, the G protein-coupled receptors (GPCRs) 6 . Compared to numerous toxins that act on voltage-gated or ligand-gated ion channels, only a few toxins that interact with GPCRs have been identified. These toxins have been isolated mainly from cone snails venoms such as conopressin interacting with vasopressin receptor 7 , contulakin-G which binds to neurotensin receptor 8 , ρ-conotoxin TIA specific of the α 1A -adrenoceptor 9 and the τ-conotoxin CnVA that interacts with the somatostatin sst3 receptor 10 . The black widow spider and the gila monster provide further examples of GPCRs interacting toxins, namely, α-latrotoxin interacting with the latrophilin receptor 11 and exenatide, exploited as an anti-diabetic drug 12 , that targets the GLP-1 receptor, respectively. In addition, mamba venoms contain aminergic toxins that recognize various bioaminergic receptors [13][14][15][16][17][18][19] . Aminergic toxins belong to the three-finger fold toxin (3FT) superfamily, a structural fold known to support a large diversity of...

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The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent

Cited by 134 publications

References 103 publications

Targeting the gastrointestinal tract to treat type 2 diabetes

Targeting the gastrointestinal tract to treat type 2 diabetes

Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Differentially Regulates Orthosteric but Not Allosteric Agonist Binding and Function

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

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