Peptide‐based multi‐agonists: a new paradigm in metabolic pharmacology

Abstract

Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. Whilst surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5-10%. An emerging class of multi-agonist drugs may eventually bridge this gap. This new class of specially tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action. Successful examples of this strategy include multi-agonist drugs targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon and the glucose-dependent insulinotropic polypeptide (GIP). Due to the simultaneous activity at several metabolically relevant receptors, these multi-agonists offer improved body weight loss and glucose tolerance relative to their constituent monotherapies. Further advancing this concept, chimeras were generated that covalently link nuclear acting hormones such as oestrogen, thyroid hormone (T ) or dexamethasone to peptide hormones such as GLP-1 or glucagon. The benefit of this strategy is to restrict the nuclear hormone action exclusively to cells expressing the peptide hormone receptor, thereby maximizing combinatorial metabolic efficacy of both drug constituents in the target cells whilst preventing the nuclear hormone cargo from entering and acting on cells devoid of the peptide hormone receptor, in which the nuclear hormone might have unwanted effects. Many of these multi-agonists are in preclinical and clinical development and may represent new and effective tools in the fight against obesity and its comorbidities.

Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH

“…Several drugs that combine GLP-1RA and other hormones—e.g., combined double co-agonism of GLP-1 receptors and glucagon, an analogue of oxyntomodulin, combination GLP-1/GIP or triple co-agonism of the of GLP-1/GIP/glucagon receptors—are in the pipeline for the treatment of T2D and obesity, and have been studied in the context of NAFLD/NASH [ 193 , 194 , 195 ] ( Table 1 and Table 3 ). GIP targets the white adipose tissue ( Figure 1 ) improving its buffering capacity by promoting postprandial triglyceride storage and fatty acids re-esterification [ 196 ].…”

Regulatory peptides and systems biology: A new era of translational and reverse‐translational neuroendocrinology

“…Parenthetically, the notion that patients might choose surgery, with all its attendant risks and complications, demonstrates hyperphagia, as a cause of obesity, to be a deeply rooted and highly physiological disorder that is resistant to simple voluntary restriction of caloric intake. This highlights the emerging understanding of eating as a potentially disordered behaviour with behavioural components that may involve the brain circuitry also implicated in addiction, such as to drugs of abuse 15,16 …”

“…The genomic niche constituted by the regulatory peptides and their receptors has clearly contributed substantially throughout the history of genetic selection (evolution), and in highly species‐specific ways, to both regulating these drives homeostatically and prioritising the behaviours driven by each. The recent development of chimeric peptides that engage multiple peptidergic receptors for controlling glucose utilisation/insulin secretion provides an example of how engaging multiple players in the regulatory peptide orchestra might yield clinically impactful results 15 . Adjudication of issues raised by clinical translation, in animal models, is a currently somewhat neglected area in regulatory peptide research.…”

Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions

“…This highlights the importance of balancing receptor interaction when developing dual or triagonists. 129 It is worth noting that there was a 30% nonresponse rate, but results would indicate that dual incretin agonists are more potent than established mono treatments 93 (Table 2).…”