Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides

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• 作者：Andrew G. Roberts ; Eric V. Johnston ; Jae-Hung Shieh ; Joseph P. Sondey ; Ronald C. Hendrickson ; Malcolm A. S. Moore ; Samuel J. Danishefsky
• 刊名：Journal of the American Chemical Society
• 出版年：2015
• 出版时间：October 14, 2015
• 年：2015
• 卷：137
• 期：40
• 页码：13167-13175
• 全文大小：790K
• ISSN：1520-5126

文摘

Human granulocyte colony-stimulating factor (G-CSF) is an endogenous glycoprotein involved in hematopoiesis. Natively glycosylated and nonglycosylated recombinant forms, lenograstim and filgrastim, respectively, are used clinically to manage neutropenia in patients undergoing chemotherapeutic treatment. Despite their comparable therapeutic potential, the purpose of O-linked glycosylation at Thr133 remains a subject of controversy. In light of this, we have developed a synthetic platform to prepare G-CSF aglycone with the goal of enabling access to native and designed glycoforms with site-selectivity and glycan homogeneity. To address the synthesis of a relatively large, aggregation-prone sequence, we advanced an isonitrile-mediated ligation method. The chemoselective activation and coupling of C-terminal peptidyl Gly thioacids with the N-terminus of an unprotected peptide provide ligated peptides directly in a manner complementary to that with conventional native chemical ligation鈥揹esulfurization strategies. Herein, we describe the details and application of this method as it enabled the convergent total synthesis of G-CSF aglycone.