Kong Xianglong, Zhang Nan, Shen Huaxing, Wang Nan, Cong Wei, Liu Chao, Hu Hong-Gang
School of Pharmacy, Weifang Medical University Weifang 261053 PR China
School of Medicine, Shanghai University Shanghai 200444 China
RSC Adv. 2023 Jul 4;13(29):19862-19868. doi: 10.1039/d3ra02743k. eCollection 2023 Jun 29.
Ascaphin-8 (GFKDLLKGAAKALVKTVLF-NH), isolated from the norepinephrine-stimulated skin secretion of the North American-tailed frog , is a C-terminal α-helical antimicrobial peptide with potential antitumor activity. However, linear peptides are difficult to be applied directly as drugs because of their inherent defects, such as low hydrolytic enzyme tolerance and poor structural stability. In this study, we designed and synthesized a series of stapled peptides based on Ascaphin-8 thiol-halogen click chemistry. Most of the stapled peptide derivatives showed enhanced antitumor activity. Among them, A8-2- and A8-4- had the most improved structural stability, stronger hydrolytic enzyme tolerance and highest biological activity. This research may provide a reference for the stapled modification of other similar natural antimicrobial peptides.
Ascaphin-8（GFKDLLKGAAKALVKTVLF-NH）是从北美尾蟾经去甲肾上腺素刺激后的皮肤分泌物中分离出来的，它是一种具有潜在抗肿瘤活性的C末端α-螺旋抗菌肽。然而，线性肽由于其固有的缺陷，如对水解酶耐受性低和结构稳定性差，难以直接作为药物应用。在本研究中，我们基于Ascaphin-8的硫醇-卤素点击化学设计并合成了一系列环化肽。大多数环化肽衍生物显示出增强的抗肿瘤活性。其中，A8-2和A8-4的结构稳定性改善最大，对水解酶的耐受性更强，生物活性最高。本研究可为其他类似天然抗菌肽的环化修饰提供参考。
