High Specificity in Protein Recognition by Hydrogen‐Bond‐Surrogate α‐Helices: Selective Inhibition of the p53/MDM2 Complex

Stabilized α-helices and nonpeptidic helix mimetics have emerged as powerful molecular scaffolds for the discovery of protein-protein interaction inhibitors.[1–8] Protein-protein interactions often involve large contact areas, which are often difficult for small molecules to target with high specificity.[9–10] The hypothesis behind the design of stabilized helices and helix mimetics is that these medium-sized molecules may pursue their targets with higher specificity because of a larger number of contacts. We recently introduced a new strategy for the preparation of stabilized α-helices, termed hydrogen bond surrogate (HBS) helices, which involves replacement of one of the main chain hydrogen bonds with a covalent linkage (Figure 1A).[11] The salient feature of the HBS approach is its ability to constrain very short peptides into highly stable α-helical conformation without blocking any molecular recognition surfaces. We have extensively analyzed the conformation adopted by HBS α-helices with 2D NMR, X-ray, and circular dichroism spectroscopies.[12–14] In addition, HBS helices have been shown to target their expected protein partners with high affinity in cell-free and cell culture assays.[15–17]