Polar hinges as functionalized conformational constraints in (bi)cyclic peptides

Protein-protein interactions (PPI’s) mediate interactions that are not only essential to homeostasis, but are also responsible for initiating and maintaining a range of physiological disorders. As a result, the inhibition of PPI's is of increasing importance to the field of drug discovery. Despite the progress that has been made in the field of PPI modulation, the development of molecules that can interfere with protein-protein interactions remains challenging. Since contact surfaces involved in PPI’s are normally large and flat, it is a serious challenge for the traditional “small-molecule” approach to effectively disrupt such a large interface. In order to address this issue, we wish to devise larger biomolecular constructs, such as cyclic peptides and peptidomimetics as PPI inhibitors. The Liskamp group has developed 'Polar hinges’ (see 'Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides, ChemBioChem, 2017, 18 (4), 387-395') as scaffolds for the cyclization of peptides, which in turn yielded bicyclic peptides and cyclized peptides with improved solubility and biological activity. During the course of this research, we noted that aqueous solubility of candidate PPI inhibitors is an absolute prerequisite not only to be able to handle and purify our target peptides; but this intrinsic property is also crucial for validation of biological activity.

Learning Objectives:

• Challenges in the development of molecules that interfere with protein-protein interactions (PPI inhibitors)
• Cyclic peptides and peptidomimetics as PPI inhibitors
• Polar hinges as scaffolds for the cyclization of peptides to yield bicyclic peptides and cyclized peptides
• Importance of aqueous solubility of candidate PPI inhibitors in the validation of biological activity

Professor Rob Liskamp
Chair of Chemical Biology and Medicinal Chemistry & Guest Professor of Molecular Medicinal Chemistry at Utrecht University
University of Glasgow & Utrecht University (The Netherlands)