Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
Nat Commun. 2021 Feb 8;12(1):870. doi: 10.1038/s41467-021-21209-0.
Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.
尽管在过去的六十年中，人们一直在努力合成具有多个二硫键的肽和蛋白质，但在大多数目标（例如，打结的小型蛋白质）中，这一合成挑战仍然是一个未解决的问题。在这里，我们展示了一种用于超快、高产形成肽和蛋白质中二硫键和三硫键的全新通用合成策略。我们开发了一种基于小分子、紫外线和钯的组合方法，用于半胱氨酸的化学和区域选择性激活，从而能够在各种肽和蛋白质中一锅法形成多个二硫键。我们制备了具有高治疗潜力的生物活性靶标，包括 conotoxin、RANTES、EETI-II 和 plectasin 肽以及 linaclotide 药物。我们预计，该策略将成为药物发现中制备数百万个难以接近的靶标的游戏规则改变者。
