Guan Xiaoyang, Chaffey Patrick K, Wei Xiuli, Gulbranson Daniel R, Ruan Yuan, Wang Xinfeng, Li Yaohao, Ouyang Yan, Chen Liqun, Zeng Chen, Koelsch Theo N, Tran Amy H, Liang Wei, Shen Jingshi, Tan Zhongping
Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado , Boulder, Colorado 80303, United States.
Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics Chinese Academy of Sciences , 15 Datun Road, Beijing 100101, People's Republic of China.
ACS Chem Biol. 2018 Jan 19;13(1):73-81. doi: 10.1021/acschembio.7b00794. Epub 2017 Dec 1.
Diabetes is a leading cause of death worldwide and results in over 3 million annual deaths. While insulin manages the disease well, many patients fail to comply with injection schedules, and despite significant investment, a more convenient oral formulation of insulin is still unavailable. Studies suggest that glycosylation may stabilize peptides for oral delivery, but the demanding production of homogeneously glycosylated peptides has hampered transition into the clinic. We report here the first total synthesis of homogeneously glycosylated insulin. After characterizing a series of insulin glycoforms with systematically varied O-glycosylation sites and structures, we demonstrate that O-mannosylation of insulin B-chain Thr27 reduces the peptide's susceptibility to proteases and self-association, both critical properties for oral dosing, while maintaining full activity. This work illustrates the promise of glycosylation as a general mechanism for regulating peptide activity and expanding its therapeutic use.
糖尿病是全球主要死因之一，每年导致超过300万人死亡。虽然胰岛素能有效控制病情，但许多患者未能遵守注射时间表，而且尽管投入巨大，仍未出现更方便的口服胰岛素制剂。研究表明，糖基化可能会稳定用于口服给药的肽，但均一糖基化肽的高要求生产阻碍了其向临床应用的转化。我们在此报告均一糖基化胰岛素的首次全合成。在对一系列具有系统变化的O-糖基化位点和结构的胰岛素糖型进行表征后，我们证明胰岛素B链Thr27的O-甘露糖基化降低了该肽对蛋白酶的敏感性和自聚集性，这两个特性对于口服给药至关重要，同时保持了完全活性。这项工作说明了糖基化作为调节肽活性和扩大其治疗用途的一般机制的前景。
