Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes

Abstract

Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9-39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.

Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

“…Furthermore, recent studies have shown that targeting multiple regulatory hormone receptors may be a viable treatment option for T2DM (Patel et al 2013, Trevaskis et al 2013, Skarbaliene et al 2015. As such, the dual activation of incretin-related pathways coupled with glucagon receptor blockade significantly improves metabolic control in diabetes (Claus et al 2007, Mu et al 2011. Given that a documented therapeutic drawback of GIP mimetics relates to elevation of glucagon levels (Meier & Nauck 2004, a combined therapy with a specific glucagon antagonist would seem logical.…”

Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2

“…Глюкагон секретируется b-клетками поджелудочной железы и стимулирует гликогенолиз и глюконеогенез в печени, что приводит к повышению уровня глюкозы в крови [49]. Создание антагонистов глюкагонового рецептора один из потенциальных подходов в терапии СД типа 2, направленный на ингибирование продукции глюкозы печенью [49][50][51].…”

“…Так был получен химерный пептид, состоящий из N-терминальной части молекулы глюкагона, соединённой с C-терминальной частью молекулы ГПП-1, который продемонстрировал высокое сродство к рецепторам. Следует отметить, что полипептид связывается как с рецептором к глюкагону, так и к ГПП-1, однако его антагонистическая активность к глюкагоновому рецептору выше, чем агонистическое действие к ГПП-1 рецептору [50]. Период полувыведения полипептида составляет менее пяти минут, что ограничивает его применение в клинической практике, поэтому были созданы пегилированные производные.…”

Biotransformation and In Vivo Stability of Protein Biotherapeutics: Impact on Candidate Selection and Pharmacokinetic Profiling

“…DAPD is vulnerable to deactivation by proteases including dipeptidyl protease IV. Due to the fast clearance of DAPD, the half-life was extended by conjugation to a high mass branched PEG (43 kDa) via maleimide conjugation through the C-terminal cysteine residue (Claus et al, 2007). By introducing the branched PEG, the in vivo half-life was significantly increased by protecting the DAPD from both catabolism and renal filtration.…”