Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Bioorg Chem. 2019 Jul;88:102945. doi: 10.1016/j.bioorg.2019.102945. Epub 2019 Apr 29.
Lytic peptides have been demonstrated to exhibit obvious advantages in cancer therapy with binding ability toward tumor cells via electrostatic attractions, which are lack of active targeting and aggregation to tumor tissue. In the present study, five conjugated lytic peptides were redesigned and constructed to target gonadotropin releasing hormone receptors (GnRHr), meanwhile, the disulfide bridge was introduced to achieve redox sensitive delivery based on the experience from the preliminary work of lytic peptides P3 and P7. YX-1, was considered to be the most promising for in-depth study. YX-1 possessed high potency (IC = 3.16 ± 0.3 μM), low hemolytic effect, and cell membrane permeability in human A2780 ovarian cancer cells. Moreover, YX-1 had prominent pro-apoptotic activity by activating the mitochondria-cytochrome c-caspase apoptotic pathway. The study yielded the conjugate YX-1 with superior properties for antineoplastic activity, which makes it a promising potential candidate for targeting cancer therapy.
溶瘤肽已被证明在癌症治疗中具有明显的优势，其通过静电吸引与肿瘤细胞结合，缺乏对肿瘤组织的主动靶向和聚集。在本研究中，设计并构建了五个共轭溶瘤肽以靶向促性腺激素释放激素受体（GnRHr），同时，根据溶瘤肽 P3 和 P7 的初步工作经验，引入二硫键以实现氧化还原敏感递药。其中，YX-1 被认为最有前途进行深入研究。在人卵巢癌细胞 A2780 中，YX-1 具有高效力（IC=3.16±0.3μM）、低溶血作用和细胞膜通透性。此外，YX-1 通过激活线粒体-细胞色素 c-半胱天冬酶凋亡途径表现出显著的促凋亡活性。该研究得到了具有抗肿瘤活性的优异特性的共轭物 YX-1，使其成为一种有前途的靶向癌症治疗的候选药物。
