Abstract
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.
Highlights
Kisspeptin receptor, that is previously known as GPR54 [1], AXOR12 [2] and hOT7T175 [3], is a member of G protein-coupled receptor (GPCR) superfamily and is coupled to Gq/11 proteins [4]
The agonistic activity of the phosphinic peptides on the kisspeptin receptor was evaluated by measuring their stimulation of the dual phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in HEK293 cells transiently expressing kisspeptin receptor
In order to explore the potential development of KP analogues with improved metabolic stability, especially with inhibition to matrix metalloproteinases (MMPs), two KP phosphinic peptides containing a replacement of the peptide bond between Gly51-Leu52 with a phosphinic acid moiety were synthesized based on the primary sequence of KPs (Figs 1 and 2)
Summary
Kisspeptin receptor, that is previously known as GPR54 [1], AXOR12 [2] and hOT7T175 [3], is a member of G protein-coupled receptor (GPCR) superfamily and is coupled to Gq/11 proteins [4]. Its endogenous ligands are firstly isolated from human placental extracts and termed either metastin (54-amino acid peptide) due to its capability to inhibit cancer metastasis [3] or kisspeptins (KPs) with different length in amino acids (54-, 14- and 13-amino acid peptides) [5]. KP-54 is cleaved from a 145-amino acid polypeptide precursor encoded by KiSS1 gene [3]. The different forms of KPs possess similar receptor binding affinity and potency [3] and share the 10 amino acids of KP-10 at their C-terminus, which are highly conserved among all vertebrate species [6]. KPs and their cognate receptor are key regulators of the mammalian reproductive system. Natural mutations of the human kisspeptin receptor lead to idiopathic hypogonadotropic
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