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Peptide therapeutics are increasingly used in the treatment of disease, but their administration by injection reduces patient compliance and convenience, especially for chronic diseases. Thus, oral administration of a peptide therapeutic represents a significant advance in medicine, but is challenged by gastrointestinal instability and ineffective uptake into the circulation. Here, we have used glucagon-like peptide-1 (GLP-1) as a model peptide therapeutic for treating obesity-linked type 2 diabetes, a common chronic disease. We describe a comprehensive multidisciplinary approach leading to the development of MEDI7219, a GLP-1 receptor agonist (GLP-1RA) specifically engineered for oral delivery. Sites of protease/peptidase vulnerabilities in GLP-1 were removed by amino acid substitution and the peptide backbone was bis-lipidated to promote MEDI7219 reversible plasma protein binding without affecting potency. A combination of sodium chenodeoxycholate and propyl gallate was used to enhance bioavailability of MEDI7219 at the site of maximal gastrointestinal absorption, targeted by enteric-coated tablets. This synergistic approach resulted in MEDI7219 bioavailability of ~ 6% in dogs receiving oral tablets. In a dog model of obesity and insulin resistance, MEDI7219 oral tablets significantly decreased food intake, body weight and glucose excursions, validating the approach. This novel approach to the development of MEDI7219 provides a template for the development of other oral peptide therapeutics.

A rationally designed peptide agonist that targets three key hormone receptors reduces obesity and its complications in a manner superior to other agonists. We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling. Trial Registration: Clinicaltrials.gov NCT01073020. Factors underlying the effects of gastric bypass surgery on glucose homeostasis are incompletely understood. Here the authors developed and applied high-throughput mediation analysis to identify proteome/metabolome mediators of improved glucose homeostasis after to gastric bypass surgery, and report that improved glycemia was mediated by the growth hormone receptor.

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule. The fusion has been engineered to deliver sustained peptide activity in vivo in combination with reduced potency, to manage GLP-1 driven adverse effects at high dose, and a favourable manufacturability profile. MEDI4166 showed robust and sustained LDL-C lowering in cynomolgus monkeys and exhibited the anticipated GLP-1 effects in T2D mouse models. We believe MEDI4166 is a novel molecule combining long acting agonist peptide and neutralising antibody activities to deliver a unique pharmacology profile for the management of T2D.

The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human β 1 - and β 3 -adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both β 1 - and β 3 -AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both β 1 - and β 3 -AR. The 3′,5′-diiodo-4′-amino analog of TMQ was the most potent β 3 -AR agonist, 17-fold more potent at the β 3 -AR versus the β 1 -AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3′,5′-diiodo-4′-acetamido analog of TMQ, a potent β 1 - and β 3 -AR agonist, abolished activity at both β-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at β 1 - and β 3 -AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at β 1 - and β 3 -AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of β 1 - and β 3 -AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent β 3 -AR agonists.

The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human β1- and β3-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both β1- and β3-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both β1- and β3-AR. The 3',5'-diiodo-4'-amino analog of TMQ was the most potent β3-AR agonist, 17-fold more potent at the β3-AR versus the β1-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3',5'-diiodo-4'-acetamido analog of TMQ, a potent β1- and β3-AR agonist, abolished activity at both β-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at β1- and β3-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at β1- and β3-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of β1- and β3-AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent β3-AR agonists. Copyright © 2001 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Trimetoquinol belongs to a novel tetrahydroisoquinoline class of compounds, and is a non-selective highly potent agonist of $\\beta$-adrenoceptors. The pharmacological activities of trimetoquinol and analogs were evaluated in rat tissues containing predominantly $\\beta\\sb1$- and $\\beta\\sb2$-adrenoceptors, and in homogeneous populations of rat $\\beta\\sb3$-, human $\\beta\\sb1$- and $\\beta\\sb3$-adrenoceptors to determine the chemical specificity for interaction with $\\beta$-adrenoceptor subtypes. The 1-benzyl diiodinated analog of trimetoquinol exhibited selectivity for the rat $\\beta\\sb3$-adrenoceptor. Pharmacological evaluation of a series of trimetoquinol analogs modified at the 1-carbon and 6,7-dihydroxybenzyl ring on homogeneous populations of human $\\beta$-adrenoceptor subtypes revealed that: (1) the diiodinated benzyl analogs displayed high affinity for the $\\beta\\sb1$- and $\\beta\\sb3$-subtypes, and high efficacy for interactions with $\\beta\\sb3$-adrenoceptors; (2) modifications of the 4$\\sp\\prime$-position of the benzyl ring gave rise to compounds which exhibited $\\beta\\sb3$-adrenoceptor selectivity, and included 3$\\sp\\prime,5\\sp\\prime$-diiodo-4$\\sp\\prime$-amino and 3$\\sp\\prime,5\\sp\\prime$-diiodo-4$\\sp\\prime$-H substituents; and (3) bioisosteric replacement of the 6,7-dihydroxybenzyl ring of trimetoquinol with a thiazolopyridine nucleus gave compounds which were selective agonists of the $\\beta\\sb3$-adrenoceptor. Selective activation of $\\beta\\sb3$-adrenoceptors is proposed to lead to enhanced lipolysis and increase in sensitivity to insulin. Thus, several of these trimetoquinol analogs represent promising leads for the development of agents that may be useful for the treatment of obesity and non-insulin dependent diabetes.

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolyl-hydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available. Footnotes * https://github.com/jdreyf/slimm-t2d-omics