The new advances in the development of chemical tools for investigating biomolecular events could provide novel molecular strategies to understand and control those events. In particular, amide-to-alkene isosteric switching in the peptide backbone is a promising approach to probe the backbone-mediated interactions, including H-bonds in the molecular recognition of peptides. Despite there are many reports of backbone modifications, there are few reports to elucidate the functional mimicry of those-type isosteres. In this study, we describe the unique ability of chloroalkene-type peptide bond isosteres to mimic the intraresidue hydrogen bonds between the carbonyl oxygen and the amide proton of the same residue. These interactions contribute significantly to the conformational stability of the beta-sheets of the amyloid state, which is linked with various neurodegenerative disorders. Kinetic studies of H/D exchange reactions of amide proton using Deg-type and Val-type compounds revealed that the chlorine atom of the (Z)-chloroalkene moiety could mimic the p-type H-bonding interaction to provide the protective effect slowing the H/D exchange reaction. In addition to the 1H-NMR and infrared spectroscopic analyses, X-ray crystallographic analysis of the peptidomimetic containing a Val-D-Ala-type (Z)-chloroalkenetype dipeptide isostere revealed that there is an attractive interaction between the amide proton and the chlorine. To the best of our knowledge, this is the first example in which the basis of C5 H-bonding mimicry of alkene-type peptide bond isosteres has been uncovered. Details of the kinetic studies, spectroscopic, and structural analyses of those isosteres will be discussed.

Intraresidue (C5) H-bonding mimicry of chloroalkene dipeptide isosteres

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.