Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues. Issue 36 (24th July 2017)

• Record Type: Journal Article
• Authors: Moroder, Luis; Musiol, Hans‐Jürgen
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 36(2017)
• Page Start: 10656
• Page End: 10669
• Publication Date: 2017-07-24
• Subjects: biosynthesis -- insulin -- native chemical ligation -- semisynthesis -- solid-phase synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201702493
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Building bridges : After a short historical overview of the discovery of insulin to its production from animal sources, and later by semi‐ and biosynthesis, this Review focuses on the most recent advances of chemical synthesis that progressively surmounted all the technical obstacles of assembling disulfide‐bridged structures via biomimetic insulin precursors in the search for analogues of improved therapeutic properties.