Synthesis and amylin receptor activity of glycomimetics of pramlintide using click chemistry

Abstract

Pramlintide (Symlin®), a synthetic analogue of the neuroendocrine hormone amylin, is devoid of the tendency to form cytotoxic amyloid fibrils and is currently used in patients with type I and type II diabetes mellitus as an adjunctive therapy with insulin or insulin analogues. As part of an on-going search for a pramlintide analogue with improved pharmacokinetic properties, we herein report the synthesis of mono- and di-glycosylated analogues of pramlintide and their activity at the AMY_1(a) receptor. Introduction of N-glycosylated amino acids into the pramlintide sequence afforded the native N-linked glycomimetics whilst use of Cu(I)-catalysed azide–alkyne 1,3-dipolar cycloaddition (click) chemistry delivered 1,2,3-triazole linked glycomimetics. AMY_1(a) receptor activity was retained by incorporation of single or multiple GlcNAc moieties at positions 21 and 35 of native pramlintide. Importantly, no difference in AMY_1(a) activity was observed between native N-linked glycomimetics and 1,2,3-triazole linked glycomimetics demonstrating that the click variants can act as surrogates for the native N-glycosides in a biological setting.