Doctoral student Alex Nazzaro (Arora Lab) describes a rapid approach to generate synthetic protein beta-sheet mimics in Angewandte Chemie. This approach is being used by Alex to develop macrocyclic peptide leads for therapeutically-important protein-protein interactions. NYU Chemistry authors include undergraduate Brandon Lu, postdoctoral fellows Nick Sawyer and Andy Watkins, and Professor Paramjit S. Arora. Read the article, etntitled "Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates" here:
Mimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. β-Sheet mimics have a storied history in bioorganic chemistry and are typically designed with synthetic or natural turn segments. We hypothesized that replacement of terminal inter-β-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic β-sheets without the requirement for natural or synthetic β-turns, thereby providing a minimal mimic of protein β-sheets. To access turn-less antiparallel β-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein β-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic–aromatic, cation-π and ionic interactions in β-sheets. In correspondence with natural β-sheets, we find that minimal HBS mimics show robust β-sheet formation when a specific pairing is incorporated. In isolated β-sheets, aromatic interactions endow superior conformational stability over ionic or cation-π interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles.