A new approach has been developed to mimic helices that occur frequently within proteins and peptides and often present an interaction site for other proteins. Such a mimetic will underpin new peptidomimetic drugs of the future.
Researchers at The University of Queensland have reported the first hydrogen bond replacement that is contained internally within a peptide, where an ethylene-linkage is in place of an internal (i,i+4) H-bond (Vernall A.J., Cassidy P., Alewood P.F., Angew. Chem., Int. Ed. 2009 [Earlyview]. The team from the University of Queensland and the UQ spinoff company Mimetica have devised a novel chemical approach to mimick helices through replacing a key hydrogen bond with a carbon-carbon bond. ‘Until now helical mimetics could not display all relevant side chains and could not be placed within a protein without the loss of potentially important residues’ Professor Alewood from the IMB said. ‘ This approach develops mimetics in the small molecule space and could provide a basis for novel peptidomimetic drugs’
The α-helix plays an important role in many biological systems, and as such much effort has been devoted to artificially stabilising this secondary peptide structure. A pentapeptide containing this covalent linkage is the smallest unit possible, and remarkably the diastereoisomer with the S configuration in the linker (see below), shows features that are characteristic of an α-helix. The team then incorporated this linkage internally within the N-terminal Galanin peptide, resulting in modified peptides with increased helicity, and thermal and proteolytic stability.
The team consisted of Peter Cassidy from Mimetica and Dr Andrea Vernall and Professor Paul Alewood from the University of Queensland. This research was supported by an ARC Linkage Grant.