Fully synthetic granulocyte colony-stimulating factor enabled by isonitrile-mediated coupling of large, side-chain-unprotected peptides Journal Article
| Authors: | Roberts, A. G.; Johnston, E. V.; Shieh, J.H.; Sondey, J. P.; Hendrickson, R. C.; Moore, M. A. S.; Danishefsky, S. J. |
| Article Title: | Fully synthetic granulocyte colony-stimulating factor enabled by isonitrile-mediated coupling of large, side-chain-unprotected peptides |
| Abstract: | 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-desulfurization strategies. Herein, we describe the details and application of this method as it enabled the convergent total synthesis of G-CSF aglycone. © 2015 American Chemical Society. |
| Keywords: | peptides; patient treatment; total synthesis; synthesis (chemical); native chemical ligation; therapeutic potentials; glycosylated; chemoselective; chemotherapeutic treatments; granulocyte-colony stimulating factor; site selectivity |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 137 |
| Issue: | 40 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-10-14 |
| Start Page: | 13167 |
| End Page: | 13175 |
| Language: | English |
| DOI: | 10.1021/jacs.5b08754 |
| PROVIDER: | scopus |
| PMCID: | PMC4617663 |
| PUBMED: | 26401918 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
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549Moore -
87Hendrickson -
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Roberts -
1
Sondey
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