Regioselective disulfide solid phase synthesis and biology of human relaxin-3, a new member of the insulin superfamily

摘要

Relaxin is a two-chain peptide member of the insulin superfamily that, in most mammals, has a key role in parturition. More recently, it has been shown to possess a number of other key biological actions. More recently, it has been demonstrated to stimulate chronotropic and inotropic responses in heart atria, and to act on the central nervous system to regulate fluid balance. It has also been shown to be a potent vasodilator as well as an antifibrotic agent suggesting that it may have potential therapeutic applications. Remarkably, a novel member of the human relaxin sub-class of the insulin superfamily was recently discovered during a Celera genomics database search and named relaxin-3 (or Gene 3 relaxin). Further searching showed the presence of murine and zebra fish equivalents indicating a probable significant biological function for the expression product. The relaxin 3 gene, Rln3, appears to be predominantly expressed in the brain, and mapping studies in the mouse indicate a highly developed network of Rln3, Rln1 and relaxin receptor-expressing cells in the brain, suggesting that relaxin peptides may have important roles in the central nervous system. Like human relaxin-2, relaxin-3 is predicted to consist of a two-chain structure and three disulfide bonds in a disposition identical to that of insulin. Importantly, it contains an Arg-X-X-X-Arg-X-X-Ile sequence within its B-chain that is known to be important for characteristic relaxin bioactivity. The primary structure of relaxin-3 is highly conserved among mammals (Fig.1). To undertake detailed biophysical and biological characterization of the peptide, its chemical synthesis was undertaken.