Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin

• DOI: 10.1021/jacs.9b11424
• Publication Date: 2019-12-18T16:35:43Z
• Authors: Mohammed Akhter H...; Ryo Okamoto; John A. Karas; Praveen Praveen; Mengjie Liu; Briony E. Forbes; John D. Wade; Yasuhiro Kajihara
• Keywords: Chemical Stability

Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin its analogues are life-saving drugs for all type I 30% II diabetic patients. However, they can readily form fibrils which a significant problem especially their use in insulin pumps. Because solubilizing hydration effects sugars, it was thought that glycosylation could inhibit fibril formation lead more stable formulation. Since enzymatic results heterogeneous products, we developed novel chemical produce homogeneous glycoinsulin (disialo-glycoinsulin) excellent yield (∼60%). It showed near-native binding affinity receptors A B vitro high glucose-lowering vivo, irrespective route administration (s.c. vs i.p.). The retained insulin-like helical structure exhibited improved stability human serum. Importantly, our disialo-glycoinsulin analogue does not at both concentration temperature. Therefore, candidate clinical