Abstract:Peptide-based analogues of the gut-derived incretin hormone,
glucagon-like
peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent
manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe
and effective in the management of Type 2 diabetes but often offer
only modest weight loss. This has prompted the search for safe and
effective alternatives to enhance the weight loss component of these
treatments. We have demonstrated that concomitant activation GLP1R
and the glucagon receptor (GCGR) c… Show more
“… Fig. 2 A The amino acid sequence of a GLP-1R/GCGR dual agonist MK1462 [ 116 ], B the amino acid sequence of the GLP-1R/GIPR dual agonist tirzepatide [ 117 ], and C the amino acid sequence of a triagonist [ 99 ]. These multiagonists are an assemblage of parts from each incretin and incorporated lessons learned from prior incretin mimetics: Aib substitute to prevent degradation by DPP4, acylation from liraglutide or semaglutide to increase solubility, and the CEX tail from exendin-4.…”
The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects.
“… Fig. 2 A The amino acid sequence of a GLP-1R/GCGR dual agonist MK1462 [ 116 ], B the amino acid sequence of the GLP-1R/GIPR dual agonist tirzepatide [ 117 ], and C the amino acid sequence of a triagonist [ 99 ]. These multiagonists are an assemblage of parts from each incretin and incorporated lessons learned from prior incretin mimetics: Aib substitute to prevent degradation by DPP4, acylation from liraglutide or semaglutide to increase solubility, and the CEX tail from exendin-4.…”
The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut–brain communication can be leveraged to achieve sustained body weight loss without adverse effects.
“…11 At Merck & Co., Inc., Kenilworth, NJ, USA, we have developed a GLP-1R/GCGR coagonist, MK-1462, with a balanced receptor activity ratio (hTone 0.9), demonstrating superior in vivo efficacy in preclinical models. 12 We envisioned that combining insulin with the GLP-1R/GCGR coagonist could induce an increase of fibroblast growth factor 21 (FGF21), 13 leading to improved insulin sensitization and an improved lipid profile, augmenting the effects of weight loss and further reducing the need for exogenous insulin. Such a combination also has the potential of an even lower hypoglycemia risk without liver targeting due to GCGR agonism.…”
mentioning
confidence: 99%
“…To design a triagonist, we leveraged our internal GLP-1R/ GCGR coagonist asset MK-1462, which demonstrated remarkable glycemic control and body weight reduction in nonhuman primate models. 12 We first sought to identify locations at the coagonist sequence for insulin attachment. By examining the GCGR-GCG complex homology model 19 that was assembled for our previous coagonist program, 12 we speculated that positions 20, 21, and 24 and the C-terminus of the peptide are not interacting with the receptor and are not solvent-exposed, making them appealing for conjugation (Figure 1).…”
mentioning
confidence: 99%
“…The first dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA tirzepatide have been approved by FDA during the submission of this paper. , Unimolecular dual agonists targeting both GLP-1 and glucagon (GCG) receptors have also been heavily investigated in the industry, trying to leverage the superior blood glucose lowering ability with GLP-1 RA and the obesity reversing potential with GCG receptor agonism . At Merck & Co., Inc., Kenilworth, NJ, USA, we have developed a GLP-1R/GCGR coagonist, MK-1462, with a balanced receptor activity ratio (hTone 0.9), demonstrating superior in vivo efficacy in preclinical models . We envisioned that combining insulin with the GLP-1R/GCGR coagonist could induce an increase of fibroblast growth factor 21 (FGF21), leading to improved insulin sensitization and an improved lipid profile, augmenting the effects of weight loss and further reducing the need for exogenous insulin.…”
mentioning
confidence: 99%
“…The strategy for assembling such an all-in-one molecule was to conjugate insulin with the GLP-1R/GCGR coagonist peptide via innovative chemistry and iterative linker design. To design a triagonist, we leveraged our internal GLP-1R/GCGR coagonist asset MK-1462, which demonstrated remarkable glycemic control and body weight reduction in nonhuman primate models . We first sought to identify locations at the coagonist sequence for insulin attachment.…”
The combination of insulin and incretin-based therapies
has emerged
as a potential promising tactic for the treatment of diabetes. Here
we report the first example of a unimolecular triagonist to simultaneously
target insulin, GLP-1, and glucagon receptors, aiming for better glycemic
control and superior weight loss. The strategy for constructing such
a unimolecular triagonist is the conjugation of the insulin moiety
and GLP-1R/GCGR coagonist peptide via alkyne–azide click chemistry.
Two tractable series differentiated by insulin conjugation sites,
B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity
comparable to that of insulin degludec and potent and balanced GLP-1R
and GCGR activities. Pharmacokinetic profiles of 13 in
both rat and minipig were also discussed.
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