Han Yusong, Chen Jia, Feng Shan, Wu Mingxuan
Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, Zhejiang Province, China.
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China.
Org Biomol Chem. 2025 Jul 23;23(29):6978-6985. doi: 10.1039/d5ob00776c.
Cyclic peptides exhibit important biological activities and are widely found in natural products and peptide-based drugs. Therefore, the development of synthesis methods for cyclic peptides is essential. In recent years, tryptophan-mediated cyclic peptides have emerged as bioactive molecules, but current methods require unique unnatural amino acids and transition metals as catalysts. Our group recently reported a tryptophan site-selective crosslinking in the protein binding pocket by sulfonium peptide single-electron transfer under UV irradiation. Herein, we expanded the reaction from intermolecular to intramolecular crosslinking to achieve peptide cyclization. This method enables the preparation of tryptophan-mediated cyclic peptides from peptides two steps: transformation of Met or Cys to dimethylsulfonium followed by crosslinking under UV irradiation with tryptophan. Therefore, this method enables synthesis using only natural amino acids, without any special catalysts. We also investigated the regioselectivity of the indole ring and found that C(6) was favoured, followed by C(4) and C(7). Next, we investigated crosslinking regioselectivity in the reader CBX1 protein binding pocket and found that C(7) was favoured, which was quite distinct from peptide cyclization. The collected data indicated that indole regioselectivity is determined by local interactions between the indole and sulfonium. Overall, this study demonstrated a feasible method for peptide cyclization using sulfonium and tryptophan. Although yield and regioselectivity are not great at the moment, we believe that this study will pave the way for future improvements based on mechanistic insights.
环肽具有重要的生物活性，广泛存在于天然产物和基于肽的药物中。因此，开发环肽的合成方法至关重要。近年来，色氨酸介导的环肽已成为生物活性分子，但目前的方法需要独特的非天然氨基酸和过渡金属作为催化剂。我们小组最近报道了在紫外线照射下，通过锍肽单电子转移在蛋白质结合口袋中进行色氨酸位点选择性交联。在此，我们将反应从分子间交联扩展到分子内交联以实现肽环化。该方法能够通过两步从肽制备色氨酸介导的环肽：将甲硫氨酸或半胱氨酸转化为二甲基锍，然后在紫外线照射下与色氨酸交联。因此，该方法仅使用天然氨基酸即可进行合成，无需任何特殊催化剂。我们还研究了吲哚环的区域选择性，发现C(6) 是有利的，其次是C(4) 和C(7)。接下来，我们研究了在读取器CBX1 蛋白结合口袋中的交联区域选择性，发现C(7) 是有利的，这与肽环化有很大不同。收集的数据表明，吲哚区域选择性由吲哚和锍之间的局部相互作用决定。总体而言，本研究展示了一种使用锍和色氨酸进行肽环化的可行方法。虽然目前产率和区域选择性并不高，但我们相信本研究将为基于机理见解的未来改进铺平道路。
