The Chemical Synthesis of Insulin: An Enduring Challenge

Abstract

The pancreatic peptide hormone insulin, first discovered exactly 100 years ago, is essential for glycemic control and is used as a therapeutic for the treatment of type 1 and, increasingly, type 2 diabetes. With a worsening global diabetes epidemic and its significant health budget imposition, there is a great demand for new analogues possessing improved physical and functional properties. However, the chemical synthesis of insulin’s intricate 51-amino acid, two-chain, three-disulfide bond structure, together with the poor physicochemical properties of both the individual chains and the hormone itself, has long represented a major challenge to organic chemists. This review provides a timely overview of the past efforts to chemically assemble this fascinating hormone using an array of strategies to enable both correct folding of the two chains and selective formation of disulfide bonds. These methods not only have contributed to general peptide synthesis chemistry and enabled access to the greatly growing numbers of insulin-like and cystine-rich peptides but also, today, enable the production of insulin at the synthetic efficiency levels of recombinant DNA expression methods. They have led to the production of a myriad of novel analogues with optimized structural and functional features and of the feasibility for their industrial manufacture.

In vivo, in vitro and in silico: an open space for the development of microbe‐based applications of synthetic biology

“…This feat was achieved with small proteins such as insulin. Today, the chemical synthesis of proteins is a difficult challenge that remains relevant, not in response to philosophical debates, but as an industrial target (Hui et al ., 2021): high‐level accuracy in the protein sequence of amino acids appears to be easier to control in vitro than in vivo (Karas et al ., 2021). The same situation prevailed with nucleic acids (Caruthers, 2013), with the same consequences in terms of industrial developments: For example, gene and vaccine syntheses require a very high precision, with accessible controls at each stage, a requirement which remains still difficult to achieve with in vivo constructs.…”

Thin Films of Lanthanide Stearates as Modifiers of the Q-Sense Device Sensor for Studying Insulin Adsorption

“…The use of this protein as a drug is still an extremely common procedure in improving the quality of life for patients with diabetes. The questions of searching for chromatographic methods for specific isolation and determination are still important. − Thin-film materials containing lanthanide atoms, as an example of nanotechnology, are actively used in many fields. − Also, materials containing lanthanide atoms are being actively studied as materials for bioorganic sensors, − including for determining the activity of insulin and analytical applications in the analysis of insulin content in complex systems. ,− Taking into account all of the problems associated with the production and application of such materials for proteomics, the purpose of this work is to demonstrate the possibility of using films containing lanthanide ions for insulin adsorption.…”

Insight on the Order of Regioselective Ultrafast Formation of Disulfide Bonds in (Antimicrobial) Peptides and Miniproteins

“…On the other hand, the chemical synthesis of small disulfide‐rich peptides and proteins (ca. 1–5 kDa), remains to be an extremely challenging task [6–11] . The main synthetic challenge in this endeavor is to selectively direct multiple disulfide bonds, due to the various S–S pairing possibilities [10] .…”