Synthesis of maleimide-braced peptide macrocycles and their potential anti-SARS-CoV-2 mechanisms,Chemical Communications

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Synthesis of maleimide-braced peptide macrocycles and their potential anti-SARS-CoV-2 mechanisms
Chemical Communications ( IF 4.3 ) Pub Date : 2022-12-12 , DOI: 10.1039/d2cc06371a
Jian Li _{1,

2} , Jina Sun _{2,

3} , Xianglei Zhang ₄ , Ruxue Zhang ₅ , Qian Wang _{1,

2} , Lin Wang ₄ , Leike Zhang ₅ , Xiong Xie _{2,

3} , Chunpu Li _{2,

3} , Yu Zhou _{2,

3} , Jiang Wang _{2,

3} , Gengfu Xiao ₅ , Fang Bai ₄ , Hong Liu _{1,

2,

3}

Affiliation

Macrocycles often exhibit good biological properties and potential druggability, which lead to versatile applications in the pharmaceutical industry. Herein, we report a highly efficient and practical methodology for the functionalization and macrocyclization of Trp and Trp-containing peptides via Pd(II)-catalyzed C–H alkenylation at the Trp C4 position. This method provides direct access to C4 maleimide-decorated Trp-containing peptidomimetics and maleimide-braced 17- to 30-membered peptide macrocycles. In particular, these unique macrocycles revealed low micro- to sub-micromolar EC₅₀ values with promising anti-SARS-CoV-2 activities. Further explorations with computational methodologies and experimental validations indicated that these macrocycles exert antiviral effects through binding with the N protein of SARS-CoV-2.

中文翻译：

马来酰亚胺支撑肽大环化合物的合成及其潜在的抗 SARS-CoV-2 机制

大环化合物通常表现出良好的生物学特性和潜在的成药性，这导致了在制药行业的广泛应用。在此，我们报告了一种高效实用的方法，用于通过Pd( II ) 催化的 Trp C4 位 C-H 烯基化对 Trp 和含 Trp 肽进行功能化和大环化。该方法提供了直接访问 C4 马来酰亚胺修饰的含有 Trp 的拟肽和马来酰亚胺支撑的 17 至 30 元肽大环化合物。特别是，这些独特的大环化合物显示出低微摩尔至亚微摩尔 EC ₅₀具有有前途的抗 SARS-CoV-2 活性的价值。对计算方法和实验验证的进一步探索表明，这些大环化合物通过与 SARS-CoV-2 的 N 蛋白结合发挥抗病毒作用。

更新日期：2022-12-12

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