From Protein-Protein Interaction Modulators to Chemical Protein Synthesis: Exploring Unconventional Approaches

Protein-protein interactions (PPIs) are associated with a wide range of crucial biological processes and targeting specific PPIs has been demonstrated to have tremendous therapeutic potential. However, PPIs – once termed as ‘undruggable’ targets, often involve large and flat binding sites along with conformational changes rendering traditional approaches ineffective. The kinetic target-guided synthesis (TGS) serves as an unconventional strategy, having the potential to streamline the development of protein-protein interaction modulators (PPIMs). In this fragment-based approach, the target is directly involved in the assembly of its own bidentate ligand from a library of reactive fragments. The first half of this seminar will focus on the application of kinetic TGS based on the sulfo-click reaction to identify PPIMs of the Bcl-2 family of proteins.
 
Chemical synthesis of proteins serves as a powerful tool for accessing these valuable biomolecules with the ability to introduce chemical modifications site-selectively. Although native chemical ligation (NCL), reported by Kent and co-workers in 1994, has been the cornerstone of chemical protein synthesis, several mechanically distinct and thiol-independent ligation reactions have also emerged in the last decade. For example, the KAHA ligation, reported by the Bode group in 2006, features a chemoselective reaction between a peptide segment bearing a C-terminal a-ketoacid and another peptide with an N-terminal hydroxylamine. Successful application of the KAHA approach through convergent ligations to accomplish total synthesis of a 184-residue ferric heme-binding protein, nitrophorin 4 (NP4) will be discussed in the second half of this seminar.