Howard Florey Institute, University of Melbourne, Melbourne, VIC 3010, Australia.
Biopolymers. 2011;96(1):81-7. doi: 10.1002/bip.21484.
Insulin-like peptide 3 (INSL3) is one of 10 members of the human relaxin-insulin superfamily of peptides. It is a peptide hormone that is expressed by fetal and postnatal testicular Leydig cells and postnatal ovarian thecal cells. It mediates testicular descent during fetal life and suppresses sperm apoptosis in adult males, whereas, in females, it causes oocyte maturation. INSL3 has also been shown to promote thyroid tumor growth and angiogenesis in human. These actions of INSL3 are mediated through its G protein-coupled receptor, RXFP2. INSL3, a two-chained peptide, binds to its receptor primarily via its B-chain, whereas elements of the A-chain are essential for receptor activation. In an attempt to design a high-affinity antagonist with potential clinical application as an anticancer agent as well as a contraceptive, we have previously prepared a synthetic parallel dimer of INSL3 B-chain and demonstrated that it binds to RXFP2 with high affinity. In this work, we undertook full pharmacological characterization of this peptide and show that it can antaogonize INSL3-mediated cAMP signaling through RXFP2. Further refinement by truncation of 18 residues yielded a minimized analogue that retained full binding affinity and INSL3 antagonism. It is an attractive lead peptide for in vivo evaluation as an inhibitor of male and female fertility and of INSL3-mediated carcinogenesis.
胰岛素样肽 3 (INSL3) 是人类松弛素-胰岛素超家族肽的 10 个成员之一。它是一种由胎儿和产后睾丸间质细胞和产后卵巢鞘细胞表达的肽类激素。它在胎儿期介导睾丸下降，并抑制成年雄性精子凋亡，而在女性中，它导致卵母细胞成熟。INSL3 还被证明可促进人类甲状腺肿瘤的生长和血管生成。INSL3 的这些作用是通过其 G 蛋白偶联受体 RXFP2 介导的。INSL3 是一种双链肽，主要通过其 B 链与受体结合，而 A 链的某些元素对于受体激活是必需的。为了设计一种具有潜在临床应用的高亲和力拮抗剂，作为抗癌剂和避孕药，我们之前已经制备了 INSL3 B 链的合成平行二聚体，并证明它与 RXFP2 具有高亲和力结合。在这项工作中，我们对该肽进行了全面的药理学表征，并表明它可以通过 RXFP2 拮抗 INSL3 介导的 cAMP 信号。通过截断 18 个残基的进一步细化得到了保留全部结合亲和力和 INSL3 拮抗作用的最小类似物。它是一种有吸引力的先导肽，可用于体内评估作为男性和女性生育力以及 INSL3 介导的致癌作用的抑制剂。
