Macrocycles have attractive pharmaceutical properties. They are especially of interest as drug leads for targets with large, flat and featureless binding sites, like protein-protein interfaces. Macrocycles are generally flexible molecules and exists as a variety of solution geometries. Describing their solution ensembles is therefore of high value. We have used macrocyclic β-hairpin peptides as model systems for studying weak interactions. Due to their resemblance to proteins, studying peptides in solution provides knowledge gained in a biologically relevant environment. Our cyclic β-hairpin model system was investigated by NMR analysis of molecular flexibility in solution (NAMFIS). We have shown that both a single interstrand hydrogen bond, as well as a single interstrand halogen bond, provides significant stabilization of the folded conformation. Further, the β-hairpin design was used for peptide inhibitors of the MDM2/p53 protein-protein interaction, and the dependence of their conformational flexibility on activity was described. Similarly, cyclic azapeptide inhibitors of the cluster of differentiation 36 (CD36) receptor were also studied with respect to conformational flexibility. Lastly, the solution conformation of the macrolide roxithromycin was described to convert from a more open structure in polar media to a more closed and less flexible in non-polar media, mimicking the cell surrounding and the cell membrane. This work demonstrates that macrocycles can be used as model systems for the study of weak interactions, which have a large influence on their conformational behavior. In addition, the obtained results show that the conformational stability of macrocycles have a high impact on their bioactivity.

Investigation of the solution conformations of macrocycles: Applications in the exploration of weak interactions and in drug design

255th National Meeting (2018)

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