Bilaterally Substituted Terphenyl Molecules Efficiently Inhibit the Interaction between a Protein and a Fully Buried α-Helix in the Malaria Parasite Motor System.

Protein-protein interactions (PPI) frequently involve α-helices and are challenging targets for small-molecule drugs. Here we report the design, synthesis and evaluation of new PPI inhibitors based on a bilaterally substituted p-terphenyl scaffold. The side groups of this scaffold are projected in a broad spatial angle and reproduced the interactions of the myosin A (MyoA) α-helix wrapped by the Myosin Tail Interacting Protein (MTIP) in Plasmodium parasites causing malaria. Fluorescence, calorimetry, and NMR spectroscopy analyses revealed that the terphenyl molecules recognized the MyoA binding site within the MTIP and were capable of displacing the α-helix from its protein receptor and triggering comparable conformational changes in MTIP. The MTIP affinity of the best inhibitor was strikingly close to that exhibited by the MyoA helix. These data indicate that a small-molecule terphenyl compound can efficiently mimic a four-times heavier polypeptide. These molecules may serve as probes for PPIs involving deeply buried α-helices.