AApeptides as a New Class of Peptidomimetics to Regulate Protein-Protein Interactions

In human physiology, proteins at all times are synthesized, processed, degraded and posttranslationally modified to varying degrees and at different rates, for their participations in a wide variety of activities to maintain normal functions of the body (Murray et al. 2007). In the successful proceedings of all the biological events, signals are consistently received and sent via physical contacts between proteins (Murray et al. 2007). The communication between proteins or the alternatively called non-covalent protein-protein interactions are thereby considered as important as proteins’ own functions (Murray et al. 2007). Disruptions of these signaling pathways by either mutational changes or deregulation of one of the protein partners would result in a series of diseases (Murray et al. 2007). On the other hand, therapeutic approaches based on chemical agents could potentially inhibit protein-protein interactions, thereby restoring the balance of signaling pathways, and leading to the cure of diseases (Murray et al. 2007). However, it is quite challenging to develop chemical agents which can target protein-protein interactions (Arkin et al. 2004; Whitty et al. 2006). Unlike the traditional medicinal chemistry approach, in which small molecule inhibitors are developed to target the hydrophobic pocket of enzymes / kinases, chemical agents are now required to bind to large surfaces of proteins that are usually amphiphilic and flexible (Murray et al. 2007). Yet a number of successful stories have been reported (Murray et al. 2007). Taking the p53/MDM2 system as an example, the p53/MDM2 has been a model system for the inhibition of protein-protein interactions, and has been reported to be the targets of a wide variety of inhibitors (Oren 1999; Balint et al. 2001; McLure et al. 2004; Brooks et al. 2006).