Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus.
Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Gabriel L
GL
Hendricks
Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106.
Kim L
KL
Weirich
Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Karthik
K
Viswanathan
Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Jing
J
Li
Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Zachary H
ZH
Shriver
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Joseph
J
Ashour
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Hidde L
HL
Ploegh
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Evelyn A
EA
Kurt-Jones
Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106; Department of Physics, University of California, Santa Barbara, California 93106.
Deborah K
DK
Fygenson
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Robert W
RW
Finberg
Charles Stark Draper Laboratory, Department of Bioengineering, Cambridge, Massachusetts 02139.
James C
JC
Comolli
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: Jennifer.Wang@umassmed.edu.
Jennifer P
JP
Wang
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D005260:Female; D006384:Hemagglutination / Q000187:drug effects; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy*; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D011134:Polysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D052736:Rous sarcoma virus / Q000187:drug effects; D029082:Sendai virus / Q000187:drug effects; D012794:Sialic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D008081:Liposomes; D011134:Polysaccharides; D012794:Sialic Acids; C581046:glycan sialylneolacto-N-tetraose c