Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone receptor-targeting peptide conjugates
Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone receptor-targeting peptide conjugates
复制标题
氧化还原敏感促性腺激素释放激素的合成及评价
DOI：
10.1016/j.bioorg.2019.102945
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Qian, Hai
中科院分区：
文献类型：
--
作者：
Dai, Yuxuan;Yue, Na;Qian, Hai
裂解肽在肿瘤治疗中具有明显的优势，具有通过静电吸引与肿瘤细胞结合的能力，但缺乏对肿瘤组织的主动靶向和聚集性。本研究以促性腺激素释放激素受体（gonadotropin releasing hormone receptor, GnRHr）为靶点，重新设计构建了5个偶联的裂解肽，同时在P3和P7裂解肽前期工作的基础上，引入二硫桥，实现氧化还原敏感递送。YX-1被认为是最有希望深入研究的。YX-1在人A2780卵巢癌细胞中具有高效（IC50 = 3.16 +/- 0.3 μ M）、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-caspase凋亡通路具有显著的促凋亡活性。该研究获得了具有优越抗肿瘤活性的缀合物YX-1，这使其成为靶向癌症治疗的有希望的潜在候选物。
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 (IC50 = 3.16 +/- 0.3 mu M), 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.