Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China.
Department of Chemistry, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu, China.
PLoS One. 2018 Apr 3;13(4):e0195089. doi: 10.1371/journal.pone.0195089. eCollection 2018.
Kisspeptins acting on their cognate G protein-coupled receptor, kisspeptin receptor, play important roles in the suppression of cancer cell metastasis and regulation of the reproductive system, and therefore are important for therapeutic intervention. All native functional human kisspeptins (kisspeptin-54, kisspsptin-14 and kisspeptin-13) share the 10 amino acids of kisspeptin-10 at their C-terminus (45-54). However, they are inactivated rapidly by matrix metalloproteinases (MMPs) through the cleavage of the peptide bond between glycine51 and leucine52, which limits their clinical applications. Development of MMP-resistant analogues of kisspeptins may provide better therapeutic outputs. In the present study, two kisspeptin phosphinic peptides were designed and synthesized, and their ability to induce phosphorylation of ERK1/2 through kisspeptin receptor and their inhibition on MMP-2 and MMP-9 whose activity correlates with cancer metastasis were assessed. The results showed that one analogue, phosphinic kisspeptin R isomer (PKPR), exhibited kisspeptin receptor-agonistic activity and also inhibitory activity on MMP-2, indicating that PKPR may serve as a lead for the further development of kisspeptin analogues for therapeutic purpose.
Kisspeptins 通过与其同源的 G 蛋白偶联受体 kisspeptin 受体发挥作用，在抑制癌细胞转移和调节生殖系统方面发挥着重要作用，因此对于治疗干预具有重要意义。所有天然功能性人类 kisspeptins（kisspeptin-54、kisspsptin-14 和 kisspeptin-13）在其 C 末端（45-54）共享 kisspeptin-10 的 10 个氨基酸。然而，它们会被基质金属蛋白酶（MMPs）迅速失活，原因是 MMPs 在甘氨酸 51 和亮氨酸 52 之间切割肽键，这限制了它们的临床应用。开发 kisspeptin 的 MMP 抗性类似物可能会提供更好的治疗效果。在本研究中，设计并合成了两种 kisspeptin 膦酸肽，并评估了它们通过 kisspeptin 受体诱导 ERK1/2 磷酸化的能力，以及它们对与癌症转移相关的 MMP-2 和 MMP-9 的抑制作用。结果表明，一种类似物，膦酸 kisspeptin R 异构体（PKPR），表现出 kisspeptin 受体激动活性，并且对 MMP-2 也具有抑制活性，表明 PKPR 可作为进一步开发用于治疗目的的 kisspeptin 类似物的先导物。
