3 years ago

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane
Kouhei Matsui, Akira Mizuno, Satoshi Shuto
Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug molecules. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell-membrane permeability for targeting protein–protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomolecules. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chemistry is described. How to get peptides to conform: Cyclopropane-based peptidomimetic approaches to mimic bioactive peptides are summarized. The functional conformations of peptides are often unknown due to their inherent conformational flexibility, which hampers the rational design of peptidomimetic molecules. This challenge is addressed by leveraging the characteristic structural features of cyclopropane in the three-dimensional diversity-oriented strategy.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201702119

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