Precisely Directing Oxidative Folding of Peptides through Artificial Disulfide Scaffolds

来源 :2016年分析化学前沿国际研讨会及中美分析化学研讨会 | 被引量 : 0次 | 上传用户:laoshuzhuimao
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  Disulfide-rich peptides are emerging as potential templates for drug design applications.However,the precise pairing of disulfide-rich peptides is a logistical nightmare for chemists trying to modulate the folding pathway.The folding process of proteins is usually described as a black art.Nature gets around the oxidative folding challenge using various redox-active proteins,however this oxidative folding problem is still puzzling chemists.Thus,it would be interesting to develop artificial disulfide-rich peptide scaffolds possessing a predictive folding pathway,which will more broadly facilitate the use of disulfide-rich scaffolds for the design of stable peptide drugs.In theory,natural peptides with three disulfide bonds have 15 possible isomers.By rationally engineering the thiol-framework of a peptide containing six cysteines with penicillamine and dithiol amino acid,we demonstrated,for the first time,that the total number of isomers formed after the oxidative folding can be decreased to a minimal of two(Figure 1).Artificial scaffolds with an intrinsic and precise disulfide pairing propensity would be more tolerant to manipulation of primary sequence than natural disulfide-rich scaffolds without the augmented function.In addition,we envisioned that artificial scaffolds would also provide new insights into mechanism of oxidative peptide/protein folding.
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