Synthesis of disulfide-rich heterodimeric peptides through an auxiliary N, N-crosslink
COMMUNICATIONS CHEMISTRY(2018)
Abstract
Insulins, relaxins, and other insulin-like peptides present a longstanding synthetic challenge due to their unique cysteine-rich heterodimeric structure. While their three disulfide signature is conserved within the insulin superfamily, sequences of the constituent chains exhibit considerable diversity. As a result, methods which rely on sequence-specific strategies fail to provide universal access to these important molecules. Biomimetic methods utilizing native and chemical linkers to tether the A-chain N-terminus to the B-chain C-terminus, entail complicated installation, and require a unique proteolytic site, or a two-step chemical release. Here we present a strategy employing a linkage of the A- and B-chains N-termini offering unrestricted access to these targets. The approach utilizes a symmetrical linker which is released in a single chemical step. The simplicity, efficiency, and scope of the method are demonstrated in the synthesis of insulin, relaxin, a 4-disulfide insulin analog, two penicillamine-substituted insulins, and a prandial insulin lispro.
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Key words
Synthetic chemistry methodology,Peptides,Chemistry/Food Science,general
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