Li Yulei, Wu Minghao, Chang Qi, Zhao Xia
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China Qingdao 266003 China.
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology Qingdao 266237 China
RSC Adv. 2018 Jun 19;8(39):22268-22275. doi: 10.1039/c8ra03446j. eCollection 2018 Jun 13.
Hymenochirin-1B is a cationic, amphipathic, α-helical host-defense peptide with 29 residues, which was isolated from skin secretions of the Congo clawed frog and showed potent cytotoxic activities against a range of tumor cell lines. However, the application of hymenochirin-1B as a drug is limited due to its conformational flexibility and poor proteolytic stability. In this research, a series of hydrocarbon-stapled analogs of hymenochirin-1B were designed, synthesized, and tested. Some analogs showed remarkable improvement not only in α-helicity, but also in antitumor activity and protease resistance when compared to the parent peptide. The results indicated that most stapled peptide analogues possessed improved activities against a series of tumor cells; in particular, the bicyclic stapled peptide H-10 showed promising prospects for novel anti-tumor drug development. Our data demonstrated the important impacts of the all-hydrocarbon crosslink stapling strategy on the biological activity, proteolytic stability and helicity of hymenochirin-1B.
膜蛙肽-1B是一种由29个氨基酸残基组成的阳离子、两亲性α-螺旋宿主防御肽，它从刚果爪蟾的皮肤分泌物中分离得到，对多种肿瘤细胞系具有强大的细胞毒活性。然而，由于其构象灵活性和较差的蛋白水解稳定性，膜蛙肽-1B作为药物的应用受到限制。在本研究中，设计、合成并测试了一系列膜蛙肽-1B的烃类环化类似物。与母体肽相比，一些类似物不仅在α-螺旋度方面有显著改善，而且在抗肿瘤活性和蛋白酶抗性方面也有显著提高。结果表明，大多数环化肽类似物对一系列肿瘤细胞具有增强的活性；特别是双环环化肽H-10在新型抗肿瘤药物开发方面显示出良好的前景。我们的数据证明了全烃交联环化策略对膜蛙肽-1B的生物活性、蛋白水解稳定性和螺旋度的重要影响。
