Amphipathic DNA polymers inhibit hepatitis C virus infection by blocking viral entry.
OBJECTIVE
Hepatitis C virus (HCV) gains entry into susceptible cells by interacting with cell surface receptor(s). Viral entry is an attractive target for antiviral development because of the highly conserved mechanism.


METHODS
HCV culture systems were used to study the effects of phosphorothioate oligonucleotides (PS-ONs), as amphipathic DNA polymers (APs), on HCV infection. The in vivo effects of APs were tested in urokinase plasminogen activator (uPA)/severe combined immunodeficient (SCID) mice engrafted with human hepatocytes.


RESULTS
We show the sequence-independent inhibitory effects of APs on HCV infection. APs were shown to potently inhibit HCV infection at submicromolar concentrations. APs exhibited a size-dependent antiviral activity and were equally active against HCV pseudoparticles of various genotypes. Control phosphodiester oligonucleotide (PO-ON) polymer without the amphipathic structure was inactive. APs had no effect on viral replication in the HCV replicon system or binding of HCV to cells but inhibited viral internalization, indicating that the target of inhibition is at the postbinding, cell entry step. In uPA/SCID mice engrafted with human hepatocytes, APs efficiently blocked de novo HCV infection.


CONCLUSIONS
Our results demonstrate that APs are a novel class of antiviral compounds that hold promise as a drug to inhibit HCV entry.
Matsumura
Takuya
T
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Hu
Zongyi
Z
Kato
Takanobu
T
Dreux
Marlene
M
Zhang
Yong-Yuan
YY
Imamura
Michio
M
Hiraga
Nobuhiko
N
Juteau
Jean-Marc
JM
Cosset
Francois-Loic
FL
Chayama
Kazuaki
K
Vaillant
Andrew
A
Liang
T Jake
TJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology*; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054735:Phosphorothioate Oligonucleotides / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014162:Transfection; D053585:Virus Attachment / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D004279:DNA, Viral; D015514:Oncogene Proteins, Fusion; D054735:Phosphorothioate Oligonucleotides; D011108:Polymers; D004247:DNA