Total Chemical Synthesis of an Intra-A-Chain Cystathionine Human Insulin Analogue with Enhanced Thermal Stability
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.
Karas, John A.,Patil, Nitin A.,Tailhades, Julien,Sani, Marc-Antoine,Scanlon, Denis B.,Forbes, Briony E.,Gardiner, James,Separovic, Frances,Wade, John D.,Hossain, Mohammed Akhter
supporting information
p. 14743 - 14747
(2016/11/23)
Nucleophilic substitution of protected 2-amino-4-butanoic acid. An easy route to exotic amino acids and conformationally constrained peptides
The synthesis of a series of novel α-amino acids based on the nucleophilic substitution of protected 2-amino-4-bromobutanoic acid (1) is described. Basic, acidic or neutral amino acids can be obtained; chimerical amino acids carrying a coenzyme type structure in the side chain, multifunctional amino acids for the synthesis of cross-linked peptides or dendrimers and conformationally constrained peptides can also be obtained.
An alternative solid-phase approach to C1-oxytocin
A general, solid-phase method based on in situ formation of a cystathionine residue is described. The procedure allows for the introduction of a thioether moiety in place of a native disulfide bond and is illustrated here by the synthesis of C1-oxytocin 1.
Mayer, John P.,Heil, James R.,Zhang, Jingwen,Munson, Mark C.
p. 7387 - 7390
(2007/10/02)
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