Transforming growth factor beta peptide antagonists and their conversion to partial agonists

Transforming growth factor beta (TGF-beta) has been implicated in the pathogenesis of various human diseases. Synthetic TGF-beta antagonists therefore could have therapeutic utility. Here we show the development of such compounds. Three synthetic pentacosapeptides designated beta(1)(25)-(41-65), beta(2)(25)-(41-65), and beta(3)(25)-(41-65), whose amino acid sequences correspond to the 41st to 65th amino acid residues of TGF-beta(1), TGF-beta(2), and TGF-beta(3), respectively, inhibit the binding of I-125-labeled TGF-beta isoforms to TGF-beta receptors in mink lung epithelial cells with IC50 of similar to 0.06-2 mu M. beta(1)(25)-(41-65) blocks TGF-beta(1)-induced growth inhibition and TGF-beta(1)-induced plasminogen activator inhibitor-1 expression in these cells. The variants designated beta(1)(25)-(41-65)W52A/D55A and beta(3)(25)-(41-65)R52A/D55A, in which both Trp(52)/Arg(52) and Asp(55) are replaced by alanine residues, do not have TGF-beta antagonist activity. Multiple conjugation of beta(1)(25)-(41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as measured by DNA synthesis inhibition. These results suggest that the (W/R)XXD motif is important for the activities of these TGF-beta peptide antagonists and that this motif may be the active site sequence of TGF-beta.