Synthesis of Four-Disulfide Insulin Analogs via Sequential Disulfide Bond Formation.
Naturally occurring, multiple cysteine-containing peptides are a structurally unique class of compounds with a wide range of therapeutic and diagnostic applications. The development of reliable, precise chemical methods for their preparation is of paramount importance to facilitate exploration of their utility. We report here a straightforward and effective approach based on stepwise, sequentially directed disulfide bond formation, exemplified by the synthesis of four-disulfide bond-containing insulin analogs. Cysteine protection consisted of tert-butylthiol (StBu), thiol-trimethoxyphenyl (STmp), trityl (Trt), 4-methoxytrityl (Mmt), S-acetamidomethyl (Acm), and tert-butyl (tBu). This report describes chemistry that is broadly applicable to cysteine-rich peptides and the influence of a fourth disulfide bond on insulin bioactivity.
Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
Fangzhou
F
Wu
Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana 46241, United States.
John P
JP
Mayer
Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana 46241, United States.
Vasily M
VM
Gelfanov
Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana 46241, United States.
Fa
0000-0002-2909-9185
F
Liu
Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.|Novo Nordisk Research Center Indianapolis, Indianapolis, Indiana 46241, United States.
Richard D
RD
DiMarchi
D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure
D004220:Disulfides; D007328:Insulin