A Synthetic Route to Human Insulin Using Isoacyl Peptides

Liu, Fa; Luo, Ethan Y.; Flora, David B.; Mezo, Adam R.

doi:10.1002/anie.201310735

Cited by 57 publications

(70 citation statements)

References 32 publications

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“…Attempts to ameliorate the synthetic routes to human insulin led Liu et al [52] to apply the isoacylconcept, which improved the synthesis of various difficult sequences. Attempts to ameliorate the synthetic routes to human insulin led Liu et al [52] to apply the isoacylconcept, which improved the synthesis of various difficult sequences.…”

Section: Angewandte Chemiementioning

confidence: 99%

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

Moröder

Musiol

2017

Angew Chem Int Ed

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After the discovery of insulin as a drug for diabetes, the pharmaceutical companies were faced with the challenge to meet the demand for insulin with the highest possible degree of purity in the required quantities from animal sources. The observation of an immune reaction of patients to insulin from animal pancreatic extracts made the availability of human insulin of highest priority. Only the enzyme-catalyzed semisynthesis at the C-terminus of the insulin B-chain led to a commercial process, but it depended on porcine insulin and was aggravated by supply concerns. The advent of rDNA technology allowed the commercial preparation of human insulin by biosynthesis in virtually unlimited quantities. An increased chemical diversity was only envisaged through chemical synthesis, which was simplified by advances in solid-phase peptide synthesis and chemical ligation. Single-chain insulin precursors are now being synthesized that should enable fast screening of insulin analogues for improved biophysical, biological, and thus promising new therapeutic properties, as well as for the industrial manufacture of insulin analogues not accessible by biosynthesis.

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Section: Angewandte Chemiementioning

confidence: 99%

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

Moröder

Musiol

2017

Angew Chem Int Ed

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“…In 2014, Liu et al. reported that the introduction of isoacyl motifs to the insulin A‐chain could drastically improve its solubility . The same effect was observed for the insulin B‐chain (Scheme A).…”

Section: Application Of Isoacyl Structural Motifs In Synthetic Peptidmentioning

confidence: 81%

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Mailig

Liu

2019

ChemBioChem

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Intramolecular N‐to‐O and O‐to‐N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl‐mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide‐bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic.

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“…The synthesis of human INSL‐6 A‐chain 2 (Scheme ) consisting of a pre‐formed CysA6‐CysA11 disulfide bond followed a procedure similar to that previously described for the preparation of the insulin A‐chain, for which CysA6‐ tert ‐butylthiol (S t Bu), CysA7‐Acm, CysA11‐ p ‐methoxytrityl (Mmt), and CysA20‐trityl (Trt) were incorporated during SPPS . The initial solid‐phase assembly of 2 resulted in poor synthetic quality, primarily due to the deletions of the TyrA2 and CysA11 residues (Figure S2 a, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…To form the CysA7‐CysB13 disulfide, the A–B heterodimer 4 was treated with 25 equivalents I 2 in aqueous acetic acid . (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Chemical Synthesis of Human Insulin‐Like Peptide‐6

Mayer

Zaykov

et al. 2016

Chemistry A European J

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Human insulin-like peptide-6 (INSL-6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL-6 utilizing fluorenylmethyloxycarbonyl-based (Fmoc) solid-phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation-sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine-mediated S-acetamidomethyl (Acm) deprotection and the second utilized iodine-free, sulfoxide-directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL-6 and will further improve synthetic access to other multiple-disulfide-containing peptides with oxidation-sensitive residues.

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A Synthetic Route to Human Insulin Using Isoacyl Peptides

Cited by 57 publications

References 32 publications

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Chemical Synthesis of Human Insulin‐Like Peptide‐6

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