Novel peptide inhibitor of ecto-ADP-ribosyl cyclase of bone marrow stromal cell antigen-1 (BST-1/CD157)

cADP-ribose, which is produced by ecto-ADP-ribosyl cyclase of CD38 or bone marrow stromal cell antigen-1 (BST-1), is a key regulator of Ca2+-induced calcium release in an Ins(1,4,5)P3-independent manner. In the present study, we have identified a specific peptide inhibitor for ADP-ribosyl cyclase of BST-1. A 15-mer random peptide phage library was screened with a soluble form of BST-1 expressed in baculovirus-infected insect cells. After biopanning, two potent sequences reactive towards BST-1 were isolated. The two synthetic peptides corresponding to the identified sequences were shown to antagonize each other's ability to inhibit the binding of the two isolated phage to BST-1, suggesting that they bind at a common binding site on BST-1. One of the peptides (SNP-1) was shown to inhibit ADP-ribosyl cyclase activity of BST-1 in an uncompetitive manner with a Ki value of 180±40 nM (n = 3). SNP-1 also inhibited cyclic ADP-ribose hydrolase activity of BST-1 dose-dependently. Selected phage did not cross-react with a soluble form of CD38. SNP-1 did not show any inhibitory effect on ADP-ribosyl cyclase activity of CD38, and therefore this peptide inhibitor will be useful to serve as a starting tool for understanding the roles of these intriguing ecto-enzymes. This is the first report of a specific ADP-ribosyl cyclase inhibitor.