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-α 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-α 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.

Keywords::

• Metalloprotease (MMP)
• tumor necrosis factor-α converting enzyme (TACE)
• enzyme inhibitor
• 3D protein structure
• inflammatory intervention

Acknowledgments

We thank Professor Xu Jiaxi for his assistance with the synthesis work. This study was supported by the National Natural Sciences Foundation of China (30371309, 30500085; Y.-Y.Z.).

Declaration of interest

We declare all support given has been mentioned above; there is no conflict of other interest.