8dpy
Synthetic Beta Sheet Macrocycle Stabilized by Hydrogen Bond SurrogatesSynthetic Beta Sheet Macrocycle Stabilized by Hydrogen Bond Surrogates
Structural highlights
Publication Abstract from PubMedMimics of protein secondary and tertiary structure offer rationally-designed inhibitors of biomolecular interactions. beta-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-beta-strand hydrogen bonds with hydrogen bond surrogates (HBS) may lead to conformationally-defined macrocyclic beta-sheets without the requirement for natural or synthetic beta-turns, thereby providing a minimal mimic of a protein beta-sheet. To access turn-less antiparallel beta-sheet mimics, we developed a facile solid phase synthesis protocol. We surveyed a dataset of protein beta-sheets for naturally observed interstrand side chain interactions. This bioinformatics survey highlighted an over-abundance of aromatic-aromatic, cation-pi and ionic interactions in beta-sheets. In correspondence with natural beta-sheets, we find that minimal HBS mimics show robust beta-sheet formation when specific amino acid residue pairings are incorporated. In isolated beta-sheets, aromatic interactions endow superior conformational stability over ionic or cation-pi interactions. Circular dichroism and NMR spectroscopies, along with high-resolution X-ray crystallography, support our design principles. Macrocyclic beta-Sheets Stabilized by Hydrogen Bond Surrogates.,Nazzaro A, Lu B, Sawyer N, Watkins AM, Arora PS Angew Chem Int Ed Engl. 2023 Oct 9;62(41):e202303943. doi: , 10.1002/anie.202303943. Epub 2023 Jun 2. PMID:37170337[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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