Given the importance of Protein-Protein Interactions (PPIs) in pharmaceutical drug discovery, special focus has been placed on the application of new structural biology methods to get a deeper understanding of this biological space. PPIs represent a new type of drug target, thus expanding the opportunity to find new chemotypes. Therefore, innovative biophysical-based approaches to address the growing demand and requirements for 1) evaluating the interactions of new chemical diversity with PPI targets and 2) structural knowledge of the PPI site to enable effective target oriented synthesis, are of paramount importance. In this context, Hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS) is a well-suited biophysical tool to study the characterization of protein dynamics following ligand binding (where the ligand is either a small molecule, a peptide or another protein). HDX-MS is emerging as a highly sensitive biophysical approach for probing PPI targets and higher-order structures.<br/>In this presentation, we report the application of HDX-MS to interrogate PPI targets in the area of cancer-immunology and autoimmune diseases. Cases in point are programmed cell death-ligand 1 (PD-L1) and interleukin-17A (IL-17A). Our results reveal that HDX-MS was able to identify the epitope mapping of PD-L1/PD-1 and IL-17A/IL-17RA which opened the way to evaluation of untested new chemical diversity. Thus, the characterization of the interactions of macrocycle peptides and phage display peptides (PPI modulators) by HDX-MS will be discussed. This work demonstrates the potential of HDX-MS as a sensitive biophysical tool to study protein-protein and protein-ligand interactions with the concomitant impact in pharmaceutical drug discovery.

Hydrogen/deuterium exchange mass spectrometry in the drug discovery scene: Application to protein-protein interactions

251st National Meeting (2016)

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