title: Molecular modeling and biological effects of peptidomimetic inhibitors of TACE activity.
abstract: We investigated the molecular basis of specificity for the interaction between tumor necrosis factor-alpha converting enzyme (TACE) and peptidomimetic inhibitors. Four novel peptidomimetic TACE inhibitors (8a-d) were designed and synthesized by introducing a substituted sulfur group and a hydrophobic group to a novel matrix metalloprotease (MMP) inhibitor. Inhibition was determined by in vitro lipopolysaccharide (LPS) cytotoxicity tests in HL-60 cell lines and by measuring the expression of mTNF-alpha using FCM techniques and immunohistochemistry in vivo. We simulated the interaction of the inhibitors with the 3D structure of the TACE active site in the Brookhaven Protein Database (PDB). The four inhibitors (8a-d) inhibited activity by 9.1%, 54.5%, 27.3%, and 54.5%, respectively. 8b and 8d showed significant in vitro inhibition in cytotoxicity tests, which corresponded to the molecular docking results. 8d also showed inhibitory activity in vivo. We explored the interface between enzyme and substrate by combining bioinformatics with experimental observations to further the development of specific TACE inhibitors to reduce inflammatory responses.
authors: Department of Chemistry, Huazhong University of Science and Technology, Wuhan, PR China. wenfang93@yahoo.com.cn
authors: Wen-fang
authors: WF
authors: Feng
authors: Yun-bin
authors: YB
authors: Zhao
authors: Wei
authors: W
authors: Huang
authors: Yu-zhen
authors: YZ
authors: Yang
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D010455:Peptides; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human