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Volume 272, Number 43, Issue of October 24, 1997 pp. 27155-27159
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Transforming Growth Factor beta  Peptide Antagonists and Their Conversion to Partial Agonists

(Received for publication, June 23, 1997, and in revised form, August 4, 1997)

Shuan Shian Huang Dagger , Qianjin Liu Dagger , Frank E. Johnson § , Yasuo Konish Dagger and Jung San Huang Dagger

From the Dagger  Department of Biochemistry and Molecular Biology and the § Department of Surgery, St. Louis University School of Medicine, St. Louis, Missouri 63104

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 125-(41-65), beta 225-(41-65), and beta 325-(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 125I-labeled TGF-beta isoforms to TGF-beta receptors in mink lung epithelial cells with IC50 of ~0.06-2 µM. beta 125-(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 125-(41-65)W52A/D55A and beta 325-(41-65)R52A/D55A, in which both Trp52/Arg52 and Asp55 are replaced by alanine residues, do not have TGF-beta antagonist activity. Multiple conjugation of beta 125-(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 .


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