TY - JOUR
T1 - Ternary nylon-3 copolymers as host-defense peptide mimics
T2 - Beyond hydrophobic and cationic subunits
AU - Chakraborty, Saswata
AU - Liu, Runhui
AU - Hayouka, Zvi
AU - Chen, Xinyu
AU - Ehrhardt, Jeffrey
AU - Lu, Qin
AU - Burke, Eileen
AU - Yang, Yiqing
AU - Weisblum, Bernard
AU - Wong, Gerard C.L.
AU - Masters, Kristyn S.
AU - Gellman, Samuel H.
N1 - Publisher Copyright:
© 2014 American Chemical Society.
PY - 2014/10/15
Y1 - 2014/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84908128615&partnerID=8YFLogxK
U2 - 10.1021/ja507576a
DO - 10.1021/ja507576a
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C2 - 25269798
AN - SCOPUS:84908128615
SN - 0002-7863
VL - 136
SP - 14530
EP - 14535
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 41
ER -