Synthesis and TGF‐β Receptor Binding Inhibition of Multibranched Compounds

Abstract

As a part of our project aiming at the discovery of novel synthetic ligands of Transforming Growth Factor Beta (TGF-b) receptors, five libraries were sequentially synthesised and screened. The biological mechanism involved in the TGF-b signal transduction proceeds through the hetero-oligomerisation of two TGF-b subreceptor dimers, Transforming growth factor Beta Receptors (TbR)-I and II. We hypothesised that synthetic dimers and multibranched-molecules could mimic the natural hormone action by closing the receptor subunits. Mimotope multipin technology was used to synthesise libraries of dimers and tetramers on solid support. This strategy led to the discovery of one of the most potent TGF-b receptor ligand on type II TGF-b receptor, described in the literature today.

Selective homodimerization of unprotected peptides using hybrid hydroxydimethylsilane derivatives

“…Dimerization strategy was applied to numerous peptide hormones including serotonin, 4,5 enkephalins, 6 bradykinin, 7 TGF-b. 8 More recently, dimerization was also applied to the design of protein-protein interaction inhibitors. 9 Several chemical strategies, in solution or on solid support, were used for peptide dimerization using specic functional groups and spacer arms.…”