title: Ternary nylon-3 copolymers as host-defense peptide mimics: beyond hydrophobic and cationic subunits.
abstract: Host-defense peptides (HDPs) are produced by eukaryotes to defend against bacterial infection, and diverse synthetic polymers have recently been explored as mimics of these natural peptides. HDPs are rich in both hydrophobic and cationic amino acid residues, and most HDP-mimetic polymers have therefore contained binary combinations of hydrophobic and cationic subunits. However, HDP-mimetic polymers rarely duplicate the hydrophobic surface and cationic charge density found among HDPs ( Hu , K. ; et al. Macromolecules 2013 , 46 , 1908 ); the charge and hydrophobicity are generally higher among the polymers. Statistical analysis of HDP sequences ( Wang , G. ; et al. Nucleic Acids Res. 2009 , 37 , D933 ) has revealed that serine (polar but uncharged) is a very common HDP constituent and that glycine is more prevalent among HDPs than among proteins in general. These observations prompted us to prepare and evaluate ternary nylon-3 copolymers that contain a modestly polar but uncharged subunit, either serine-like or glycine-like, along with a hydrophobic subunit and a cationic subunit. Starting from binary hydrophobic-cationic copolymers that were previously shown to be highly active against bacteria but also highly hemolytic, we found that replacing a small proportion of the hydrophobic subunit with either of the polar, uncharged subunits can diminish the hemolytic activity with minimal impact on the antibacterial activity. These results indicate that the incorporation of polar, uncharged subunits may be generally useful for optimizing the biological activity profiles of antimicrobial polymers. In the context of HDP evolution, our findings suggest that there is a selective advantage to retaining polar, uncharged residues in natural antimicrobial peptides.
authors.affiliation: Department of Chemistry, ‡Department of Biomedical Engineering, and §Department of Medicine, University of Wisconsin , Madison, Wisconsin 53706, United States.
authors.forename: Saswata
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Runhui
authors.initials: R
authors.lastname: Liu
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ehrhardt
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.forename: Eileen
authors.initials: E
authors.lastname: Burke
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Yang
authors.forename: Bernard
authors.initials: B
authors.lastname: Weisblum
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
authors.forename: Kristyn S
authors.initials: KS
authors.lastname: Masters
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D002412:Cations / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D002412:Cations; D010455:Peptides; D011108:Polymers