ArticleJournal of the American Chemical Society2013
Fully convergent chemical synthesis of ester insulin: determination of the high resolution X-ray structure by racemic protein crystallography.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 82 citations in OpenAlex.
- Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity.Communications chemistry · 2023Article
- Synthesis and applications of mirror-image proteins.Nature reviews. Chemistry · 2023Review
- D-Peptide and D-Protein Technology: Recent Advances, Challenges, and Opportunities.Chembiochem : a European journal of chemical biology · 2023Review
- Semisynthesis of Aminomethyl-Insulin: An Atom-Economic Strategy to Increase the Affinity and Selectivity of a Protein for Recognition by a Synthetic Receptor.Bioconjugate chemistry · 2023Article
- The rippled β-sheet layer configuration-a novel supramolecular architecture based on predictions by Pauling and Corey.Chemical science · 2022Article
- A crystal-structural study of Pauling-Corey rippled sheets.Chemical science · 2022Article
- Solid-Phase Synthesis of Head to Side-Chain Tyr-Cyclodepsipeptides Through a Cyclative Cleavage From Fmoc-MeDbz/MeNbz-resins.Frontiers in chemistry · 2020Article
- Atomic-level engineering and imaging of polypeptoid crystal lattices.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Substitution of an Internal Disulfide Bridge with a Diselenide Enhances both Foldability and Stability of Human Insulin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2019Article
- Homochiral and racemic MicroED structures of a peptide repeat from the ice-nucleation protein InaZ.IUCrJ · 2019Article
- Novel protein science enabled by total chemical synthesis.Protein science : a publication of the Protein Society · 2019Review
- Facile folding of insulin variants bearing a prosthetic C-peptide prepared by α-ketoacid-hydroxylamine (KAHA) ligation.Chemical science · 2018Article
- Chemically Precise Glycoengineering Improves Human Insulin.ACS chemical biology · 2018Article
- Glucose-responsive insulin by molecular and physical design.Nature chemistry · 2017Article
- Reinvestigation of the biological activity of d-allo-ShK protein.The Journal of biological chemistry · 2017Article
- Scope and Limitations of Fmoc Chemistry SPPS-Based Approaches to the Total Synthesis of Insulin Lispro via Ester Insulin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2017Article
- Pursuit of a perfect insulin.Nature reviews. Drug discovery · 2016Review
- Efficient Total Chemical Synthesis of (13) C=(18) O Isotopomers of Human Insulin for Isotope-Edited FTIR.Chembiochem : a European journal of chemical biology · 2016Article
- High-resolution structures of a heterochiral coiled coil.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- An oxazetidine amino acid for chemical protein synthesis by rapid, serine-forming ligations.Nature chemistry · 2015Article
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6 authors at 2 institutions in 1 country.
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Abstract
Efficient total synthesis of insulin is important to enable the application of medicinal chemistry to the optimization of the properties of this important protein molecule. Recently we described "ester insulin"--a novel form of insulin in which the function of the 35 residue C-peptide of proinsulin is replaced by a single covalent bond--as a key intermediate for the efficient total synthesis of insulin. Here we describe a fully convergent synthetic route to the ester insulin molecule from three unprotected peptide segments of approximately equal size. The synthetic ester insulin polypeptide chain folded much more rapidly than proinsulin, and at physiological pH. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin (i.e., [Asp(B10), Lys(B28), Pro(B29)]ester insulin) were prepared by total chemical synthesis. The atomic structure of the synthetic ester insulin molecule was determined by racemic protein X-ray crystallography to a resolution of 1.6 Å. Diffraction quality crystals were readily obtained from the racemic mixture of {D-DKP ester insulin + L-DKP ester insulin}, whereas crystals were not obtained from the L-ester insulin alone even after extensive trials. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin were assayed for receptor binding and in diabetic rats, before and after conversion by saponification to the corresponding DKP insulin enantiomers. L-DKP ester insulin bound weakly to the insulin receptor, while synthetic L-DKP insulin derived from the L-DKP ester insulin intermediate was fully active in binding to the insulin receptor. The D- and L-DKP ester insulins and D-DKP insulin were inactive in lowering blood glucose in diabetic rats, while synthetic L-DKP insulin was fully active in this biological assay. The structural basis of the lack of biological activity of ester insulin is discussed.
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