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
Altmetric Score
MSK Authors
  1. Jae-Hung Shieh
    68 Shieh
  2. Malcolm A S Moore
    414 Moore
  3. Joseph Paul Sondey
    1 Sondey