title: Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability.
abstract: Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded oligomers. Consequently we examined the utility of the non-reducible cystine isostere, cystathionine, within the A-chain. Reported herein is an efficient method for forming this mimic using simple monomeric building blocks. The intra-A-chain cystathionine insulin analogue was obtained in good overall yield, chemically characterized and demonstrated to possess native binding affinity for the insulin receptor isoform B. It was also shown to possess significantly enhanced thermal stability indicating potential application to next-generation insulin analogues.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.|CSIRO, Materials Science and Engineering, Clayton, VIC, 3010, Australia.
authors.forename: John A
authors.identifier: 0000-0002-3800-5152
authors.initials: JA
authors.lastname: Karas
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Nitin A
authors.identifier: 0000-0003-0422-9411
authors.initials: NA
authors.lastname: Patil
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Julien
authors.identifier: 0000-0003-0391-2526
authors.initials: J
authors.lastname: Tailhades
authors.affiliation: School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Marc-Antoine
authors.identifier: 0000-0003-3284-2176
authors.initials: MA
authors.lastname: Sani
authors.affiliation: Department of Chemistry, University of Adelaide, Adelaide, SA, 5005, Australia.
authors.forename: Denis B
authors.identifier: 0000-0003-0960-8197
authors.initials: DB
authors.lastname: Scanlon
authors.affiliation: School of Medicine, Flinders University, Bedford Park, SA, 5042, Australia.
authors.forename: Briony E
authors.identifier: 0000-0003-4360-9927
authors.initials: BE
authors.lastname: Forbes
authors.affiliation: CSIRO, Materials Science and Engineering, Clayton, VIC, 3010, Australia.
authors.forename: James
authors.identifier: 0000-0003-0298-5790
authors.initials: J
authors.lastname: Gardiner
authors.affiliation: School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Frances
authors.identifier: 0000-0002-6484-2763
authors.initials: F
authors.lastname: Separovic
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: John D
authors.identifier: 0000-0002-1352-6568
authors.initials: JD
authors.lastname: Wade
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.|School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
authors.forename: Mohammed Akhter
authors.identifier: 0000-0002-9961-0006
authors.initials: MA
authors.lastname: Hossain
mesh_terms: D003540:Cystathionine / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000737:chemistry*; D008968:Molecular Conformation; D013696:Temperature
chemical_list: D007328:Insulin; D003540:Cystathionine
keywords: cystathionine; cystine; diabetes mellitus; insulin; solid-phase peptide synthesis