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Review
. 2013 Jul 22;52(30):7646-65.
doi: 10.1002/anie.201301666. Epub 2013 Jun 17.

The winding pathway to erythropoietin along the chemistry-biology frontier: a success at last

Rebecca M Wilson  1 , Suwei Dong, Ping Wang, Samuel J Danishefsky
Affiliations
Review

The winding pathway to erythropoietin along the chemistry-biology frontier: a success at last

Rebecca M Wilson et al. Angew Chem Int Ed Engl. .

Abstract

The total synthesis of a homogeneous erythropoietin (EPO), possessing the native amino acid sequence and chitobiose glycans at each of the three wild-type sites of N glycosylation, has been accomplished in our laboratory. We provide herein an account of our decade-long research effort en route to this formidable target compound. The optimization of the synergy of the two bedrock sciences we now call biology and chemistry was central to the success of the synthesis of EPO.

Keywords: amino acids; erythropoietin; glycoprotein; synthetic methods; total synthesis.

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Figures

Figure 1
Figure 1
Ribbon structure of EPO containing a consensus sequence of N- and O-linked carbohydrate domains.
Figure 2
Figure 2
Structures of oligosaccharides employed in this review.
Figure 3
Figure 3
First generation strategy toward EPO.
Figure 4
Figure 4
The image of human burst forming unit-erythrocyte (BFU-E) colony. 60 ngmL−1 synthetic folded EPO (109) and 20 ngmL−1 rhKL stimulate purified cord blood CD34 cells to form BFU-E colony after 2 weeks
Scheme 1
Scheme 1
Glycopeptide–Peptide Ligation Strategy.
Scheme 2
Scheme 2
Demonstration of a Novel Glycopeptide–Peptide Ligation Protocol.
Scheme 3
Scheme 3
Glycopeptide–Glycopeptide Ligation Strategy.
Scheme 4
Scheme 4
Demonstration of a Glycopeptide–Glycopeptide Ligation Protocol.
Scheme 5
Scheme 5
Synthesis of EPO(22–37).
Scheme 6
Scheme 6
OMER Strategy for Auxiliary-Based Non-Cysteine Ligation.
Scheme 7
Scheme 7
Demonstration of OMER-Based Auxiliary Protocol.
Scheme 8
Scheme 8
Tether Strategy for Auxiliary-Based Non-Cysteine Ligation.
Scheme 9
Scheme 9
Demonstration of Tether Strategy: Synthesis of EPO(114–166). K = Lys(ivDde).
Scheme 10
Scheme 10
Reiterative Ligation Strategy.
Scheme 11
Scheme 11
Demonstration of Reiterative Ligation.
Scheme 12
Scheme 12
Glycopeptide Fragment Coupling Strategy.
Scheme 13
Scheme 13
Demonstration of Glycopeptide Fragment Coupling.
Scheme 14
Scheme 14
Auxiliary-Free Non-Cysteine Ligation: A Metal-Free Dethiylation Protocol.
Scheme 15
Scheme 15
First-Generation Synthetic Strategy Toward EPO.
Scheme 16
Scheme 16
Synthesis of EPO(78–166).
Scheme 17
Scheme 17
Synthesis of EPO(29–77).
Scheme 18
Scheme 18
Synthesis of EPO(1–28).
Scheme 19
Scheme 19
Second-Generation Synthetic Strategy Toward EPO.
Scheme 20
Scheme 20
Synthesis of EPO(79–166).
Scheme 21
Scheme 21
Proposed Solution to the Problem of Aspartimide Formation in Lansbury Aspartylation.
Scheme 22
Scheme 22
Demonstration of Aspartylation Protocol: Synthesis of EPO Glycopeptide Fragments.
Scheme 23
Scheme 23
Total Synthesis of the EPO Primary Structure.
Scheme 24
Scheme 24
Total Synthesis of Folded EPO.
Scheme 25
Scheme 25
Total Synthesis of Folded non-glyco EPO.
See this image and copyright information in PMC

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