Design and synthesis of peptidomimetic molecules targeting cadherin-mediated protein-protein interactions

Cadherins are cell-cell adhesion proteins which are overexpressed in several solid tumors. They contain an extracellular region consisting of five immunoglobulin-like domains (EC1–EC5) that extend from the cell surface. In 1995, structural data of the N-cadherin suggested an homodimeric interface involving the peptide chains HAVDI and INPI contained in the middle EC1 sequence. Based on these studies, mimics of His-Ala-Val sequence have been patented. More recently, the crystal structures of the complete (EC1-EC5) ectodomains of N- and E-cadherins have been solved highlighting that cadherins dimerize through a ‘strand-swap’ trans-adhesive interface involving the N-terminal EC1 domains. In this framework, a thorough study of the adhesion dimer structures was attempted with the aim of characterizing cadherin binding interfaces and developing computational tools for the design of small peptidomimetics that target the homophilic interactions of the extracellular cadherin domains. The communication will discuss the first results obtained in the computer-aided design, the synthesis of the most promising peptidomimetics according to the virtual screening protocols and their preliminary biological evaluation.