DPP‐IV‐resistant, long‐acting oxyntomodulin derivatives

Abstract

Obesity is one of the major risk factors for type 2 diabetes, and the development of agents, that can simultaneously achieve glucose control and weight loss, is being actively pursued. Therapies based on peptide mimetics of the gut hormone glucagon-like peptide 1 (GLP-1) are rapidly gaining favor, due to their ability to increase insulin secretion in a strictly glucose-dependent manner, with little or no risk of hypoglycemia, and to their additional benefit of causing a modest, but durable weight loss. Oxyntomodulin (OXM), a 37-amino acid peptide hormone of the glucagon (GCG) family with dual agonistic activity on both the GLP-1 (GLP1R) and the GCG (GCGR) receptors, has been shown to reduce food intake and body weight in humans, with a lower incidence of treatment-associated nausea than GLP-1 mimetics. As for other peptide hormones, its clinical application is limited by the short circulatory half-life, a major component of which is cleavage by the enzyme dipeptidyl peptidase IV (DPP-IV). SAR studies on OXM, described herein, led to the identification of molecules resistant to DPP-IV degradation, with increased potency as compared to the natural hormone. Analogs derivatized with a cholesterol moiety display increased duration of action in vivo. Moreover, we identified a single substitution which can change the OXM pharmacological profile from a dual GLP1R/GCGR agonist to a selective GLP1R agonist. The latter finding enabled studies, described in detail in a separate study (Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capitò E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009; 58: 2258-2266), which highlight the potential of GLP1R/GCGR dual agonists as a potentially superior class of therapeutics over the pure GLP1R agonists currently in clinical use.

A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice

“…YAGglucagon markedly increased in vitro insulin secretion in BRIN-BD11 cells under both physiological and supraphysiological glucose conditions. This is an interesting finding, as potency was better than glucagon per se, suggesting that the actions of YAG-glucagon to enhance insulin production may be as a result of a stimulatory effect on related receptors including GIP and possibly GLP-1, as is the case with other proglucagon-derived peptides [10][11][12][13][14][15][16][17]. each of the receptor-transfected cell lines, cAMP responses indicated that there was cross-talk at each of the receptors, but these effects were less than those evoked by 10 6 times lower concentration of the native peptides.…”

“…First-strand cDNA was synthesised using 2 μg total RNA at 42°C for 50 min in the presence of 0.5 μg oligo-dT (12)(13)(14)(15)(16)(17)(18) ÀΔC t values normalised to rat β-actin control primer.…”

“…Thus oxyntomodulin analogues and peptides designed to trigger both glucagon and GLP-1 receptors represent unexpected therapeutic agents [12][13][14][15][16][17]. Glucose-dependent insulinotropic polypeptide (GIP), also from the glucagon/secretin family of peptides [2], is the major physiological incretin with powerful insulin-releasing and glucose-lowering properties, which may also have therapeutic potential [18].…”

Small Molecule Allosteric Modulation of the Glucagon-Like Peptide-1 Receptor Enhances the Insulinotropic Effect of Oxyntomodulin

“…For example, additional experiments are needed to explore the overall therapeutic consequence of preferentially enhancing cAMP signaling versus other pathways. Likewise, chronic studies are necessary to determine whether enhancing oxyntomodulin action on the GLP-1 receptor in the CNS improves energy metabolism leading to weight loss, a phenomenon shown for parenterally administered, long-acting oxyntomodulin analogs (Pocai et al, 2009;Santoprete et al, 2011). A possible option for future long-term studies is to characterize the receptor binding properties and signal transduction capabilities of a recently disclosed quinoxaline analog.…”

“…The half-life of GLP-1(7-36)-NH 2 /(7-37) is 1 to 2 min (Siegel et al, 1999), whereas half-life estimates for oxyntomodulin range from 6 to 12 min Schjoldager et al, 1988;Kervran et al, 1990). Furthermore, infusion studies in humans confirm the metabolic actions of oxyntomodulin (Cohen et al, 2003), and new drug discovery approaches to develop long-acting analogs of oxyntomodulin are being pursued (Pocai et al, 2009;Santoprete et al, 2011). Whereas such molecules show initial success, these are peptide-based and require subcutaneous injection.…”