Facile folding of insulin variants bearing a prosthetic C-peptide prepared by -ketoacid-hydroxylamine (KAHA) ligation

被引：18

作者：

Boross, Gabor N. ^{[1
]}

Shimura, Satomi ^{[1
]}

Besenius, Melissa ^{[2
]}

Tennagels, Norbert ^{[2
]}

Rossen, Kai ^{[2
,3
]}

Wagner, Michael ^{[2
]}

Bode, Jeffrey W. ^{[1
]}

机构：

[1] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Lab Organ Chem, CH-8093 Zurich, Switzerland

[2] Sanofi Aventis Deutschland GmbH, Ind Pk Hoechst, D-65926 Frankfurt, Germany

[3] H Lundbeck & Co AS, Ottiliavej 9, DK-2500 Valby, Denmark

来源：

CHEMICAL SCIENCE | 2018年 / 9卷 / 44期

关键词：

CHEMICAL-SYNTHESIS; BIOMIMETIC SYNTHESIS; ESTER INSULIN; PROINSULIN; GLARGINE;

D O I：

10.1039/c8sc03738h

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The chemical synthesis of insulin is an enduring challenge due to the hydrophobic peptide chains and construction of the correct intermolecular disulfide pattern. We report a new approach to the chemical synthesis of insulin using a short, traceless, prosthetic C-peptide that facilitates the formation of the correct disulfide pattern during folding and its removal by basic treatment. The linear precursor is assembled by an ester forming -ketoacid-hydroxylamine (KAHA) ligation that provides access to the linear insulin precursors in good yield from two readily prepared segments. This convergent and flexible route provides access to various human, mouse, and guinea pig insulins containing a single homoserine mutation that shows no detrimental effect on the biological activities.

引用

页码：8388 / 8395

页数：8