Water-soluble polypeptides that adopt stable a-helical conformations have long been sought after.   Tremendous efforts have been focused on introducing neutrally charged, hydrophilic functional groups or moieties. For instance, poly(N-hydroxyalkyl-L-glutamine),  derived fromaminolysis of poly(L-glutamate ester) (PLG), was found to be water-soluble due to its pendant hydroxyl groups.  It adopts moderately high helical structure (up to ca. 65% helicity) in aqueous solution.  Deming and co-workers reported the synthesis of PLL containing pendant oligoethyleneglycol moieties via the ring-opening polymerisation of oligoethyleneglycol-containing lysine N-carboxyanhdyride (NCA). The resulting oligoethyleneglycol-graft PLL showed excellent water-solubility and up to ca. 100% helical structure in pH 7 water at 25 oC.   These polypeptides were designed in a manner to introduce water-soluble motifs on a a-helical structure in the absence of electrostatic perturbations.  To our knowledge, charged, water-soluble polypeptides that adopt stable a-helical conformations, i.e., a-helical polypeptide electrolytes (a-HPEs), have never been reported.    In this study, we prepared a series of PLG analogues with extented, hydrophobic side chains bearing a terminal, positively charged amine group.  When the amine group is placed 11 s-bonds away from the polypeptide backbones, the corresponding polypeptide bearing positive charges on its side chains indeed showed remarkable a-helical conformations crossing a broad range of pH (from 1 to 10).    This design principle has been applied to the synthesis of a handful of polypeptides with similar side chain strucutres and has been confirmed as these polypeptides all possess a-helical conformations with unusual helical stability against changing environmental conditions.

Development of ionic, helical polypeptides

242nd National Meeting (2011)

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