Eleven Amino Acid Glucagon-like Peptide-1 Receptor Agonists with Antidiabetic Activity

Mapelli, Claudio; Natarajan, Sesha; Meyer, J.‐P.; Bastos, Margarita; Bernatowicz, Michael S.; Lee, Ving G.; Pluščec, Jelka; Riexinger, Douglas; Sieber-McMaster, Ellen; Constantine, Keith L.; Smith-Monroy, Constance; Golla, Rajasree; Ma, Zhengping; Longhi, Daniel Angelo; Shi, Dan; Li, Xin; Taylor, Joseph R.; Koplowitz, Barry; Cecilia, Laura Varone; Khanna, Ashish K.; Robinson, Gordon W.; Seethala, Ramakrishna; Antal‐Zimanyi, Ildiko; Stoffel, Robert H.; Han, Song‐Ping; Whaley, Jean M.; Huang, Christine; Krupinski, John; Ewing, William R.

doi:10.1021/jm900752a

Cited by 63 publications

(53 citation statements)

References 41 publications

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“…It may well be that the correct spatial orientation of Phe 22 to the pocket in the receptor triggers conformational change in the receptor that affects the relative orientation of the N-terminal and transmembrane domains. This may also explain why much smaller 11-residue peptides, which share the N-terminal portion of GLP-1/Ex-4 but have various biphenyl and/or phenylalanine derivatives at the C-terminal end, achieve similar activation profiles to that of GLP-1 and Ex-4 (28,47,48). It is possible that, for these compounds, the biphenyl derivatives bind to the same pocket as Phe 22 in GLP-1/Ex-4 and trigger a conformational change in the receptor that allows the N terminus of these shorter peptides to interact with the core of the receptor.…”

Section: Discussionmentioning

confidence: 99%

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro

Swedberg

Schroeder

Mitchell

et al. 2016

Journal of Biological Chemistry

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Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide ␣-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe 22 into a hydrophobic pocket on the GLP-1R.Secretion of insulin is considerably higher in response to oral administration of glucose compared with intravenous delivery (1). This phenomenon, known as the "incretin effect," is primarily mediated by two peptide hormones called incretins: glucagon like peptide 1 (GLP-1) 5 (2) and glucose-dependent insulinotropic polypeptide (3). The incretin effect is often greatly reduced in patients suffering from type 2 diabetes mellitus (4), and a possible therapeutic approach for this condition is incretin supplement therapy. Because type 2 diabetes mellitus sufferers continue to respond to GLP-1, but not to glucose-dependent insulinotropic polypeptide (5), recent therapeutic supplement strategies have focused on GLP-1 and the development of synthetic analogs (6).GLP-1 exerts its physiological activity in the 0.1-1 nM range (7) by signaling through the glucagon-like peptide-1 receptor (GLP-1R), a secretin/family B of G protein-coupled receptors (GPCR) (8). Primary GLP-1R signaling occurs via binding to G ␣ subunits that activate the intracellular cAMP pathway. Additional signaling also occurs via both ␤-arrestin and mobilization of intracellular calcium. Indeed, the level of variability in response reflects the diverse physiological functions of GLP-1R in different tissues (9). As with other members of GPCR receptor family, the GLP-1R has a large extracellular N...

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Section: Discussionmentioning

confidence: 99%

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro

Swedberg

Schroeder

Mitchell

et al. 2016

Journal of Biological Chemistry

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“…Small molecule GLP-1 ligands BETP (Sloop et al, 2010), Compound 2 (Knudsen et al, 2007), Boc5 (Chen et al, 2007), [(2S)-2-[[(8S)-7-benzoyl-3-[4-[(3,4-dichlorophenyl) (Rao, 2009), and BMS21 (Mapelli et al, 2009) were synthesized according to literature and standard methods (see Supplemental Data, experimental procedure for more details). GLP-1(7-36)NH 2 , GLP-1(1-36)NH 2 , exendin-4, and oxyntomodulin were purchased from American Peptide Company (Sunnyvale, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Like most GPCRs, the GLP-1R couples to different classes of heterotrimeric G proteins, including Ga s , Ga q , and Ga i , as well as various other signaling and regulatory proteins such as the b-Arrs. In this study, the selective GLP-1R small molecules, BETP (Sloop et al, 2010), Compound 2 (Knudsen et al, 2007), TT15 (Rao, 2009), Boc5 (Chen et al, 2007), and a modified GLP-1 analog (BMS21) (Mapelli et al, 2009) (Fig. 1) were assessed for their ability to activate various intracellular signaling pathways.…”

Section: Small Molecules Ligands and Peptides Differentiallymentioning

confidence: 99%

Differential Activation and Modulation of the Glucagon-Like Peptide-1 Receptor by Small Molecule Ligands

et al. 2013

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The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for the treatment of type 2 diabetes due to its role in glucose homeostasis. Despite the availability of peptide-based GLP-1R drugs for treatment of this disease, there is great interest in developing small molecules that can be administered orally. The GLP-1R system is complex, with multiple endogenous and clinically used peptide ligands that exhibit different signaling biases at this receptor. This study revealed that small molecule ligands acting at this receptor are differentially biased to peptide ligands and also from each other with respect to the signaling pathways that they activate. Furthermore, allosteric small molecule ligands were also able to induce bias in signaling mediated by orthosteric ligands. This was dependent on both the orthosteric and allosteric ligand as no two allosteric-orthosteric ligand pairs could induce the same signaling profile. We highlight the need to profile compounds across multiple signaling pathways and in combination with multiple orthosteric ligands in systems such as the GLP-1R where more than one endogenous ligand exists. In the context of pleiotropical coupling of receptors and the interplay of multiple pathways leading to physiologic responses, profiling of small molecules in this manner may lead to a better understanding of the physiologic consequences of biased signaling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signaling, leading to beneficial therapeutic outcomes while reducing side effect profiles.

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“…A series of eleven-amino acid peptide, agonists of the GLP-1R, have been reported to have excellent potency and in vivo activity in ob/ob mouse models of diabetes [123,124]. These peptides are closely related structurally to nine C-terminal residues of GLP-1 but are substituted with several unnatural amino acids at position 11, such as homohomophenylalanine.…”

Section: Glp-1 Based Therapiesmentioning

confidence: 99%

“…This gives rise to the opportunity to increase stability against proteolytic degradation by DPP-IV. However, the activity of these peptides can be blocked with inactive exendin (9-39) (exendin antagonist) [124].…”

Section: Glp-1 Based Therapiesmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Thompson¹

2013

Clin Exp Pharmacol

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It has been estimated that approximately 8.4% of the world population currently live with diabetes mellitus and type 2 diabetes is the most common form. Type 2 diabetes increases the risk of complications such as heart attacks, blindness, amputations and kidney failure. Glucagon like Peptide-1 (GLP-1) is an effective insulinotropic agent and therefore its effects on insulin secretion have been greatly examined for more than two decades. It is a polypeptide hormone secreted by the intestinal L-cells into the blood in response to food uptake. GLP-1 has a very short half-life in vivo due to the rapid proteolytic degradation by Dipeptidyl Peptidase IV (DPP-IV). Therefore DPP-IV resistant GLP-1 analogues, Exenatide and Liraglutide, have been developed and are currently being used in the treatment of type 2 diabetes. GLP-1 agonist functions by binding to its receptor, GLP1R, on the cell surface.The GLP-1R belongs to the class B peptide receptor family based on its structure and function. The binding of GLP-1 to its receptor results in activation of Gαs coupled adenylyl cyclase and the production of cyclic Adenosine Monophosphate (cAMP), which enhances glucose-induced insulin secretion. Continuous GLP-1R activation also causes insulin secretion and pancreatic islet β-cell proliferation and neogenesis. The GLP-1R is internalised following its activation, which regulates the biological responsiveness of the receptor. Structurally the GLP-1R contains a large N-terminal extracellular domain (TM1-TM7) joined by three intracellular loops (ICL1, ICL2, ICL3) and three extracellular loops (ECL1, ECL2, ECL3), and an intracellular C-terminal domain. These domains play critical roles in GLP-1R trafficking to the cell surface, and also in agonist dependent activation and internalisation of the receptor. This review is focused on type 2 diabetes, its treatment with GLP-1, GLP-1R structure and function, and the physiological affects resulting from GLP-1R activation.

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Eleven Amino Acid Glucagon-like Peptide-1 Receptor Agonists with Antidiabetic Activity

Cited by 63 publications

References 41 publications

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro

Truncated Glucagon-like Peptide-1 and Exendin-4 α-Conotoxin pl14a Peptide Chimeras Maintain Potency and α-Helicity and Reveal Interactions Vital for cAMP Signaling in Vitro

Differential Activation and Modulation of the Glucagon-Like Peptide-1 Receptor by Small Molecule Ligands

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

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