Amphipathic DNA Polymers Inhibit Hepatitis C Virus Infection by Blocking Viral Entry

Matsumura, Takuya; Hu, Zongyi; Kato, Takanobu; Dreux, Marlène; Zhang, Yong–Yuan; Imamura, Michio; Hiraga, Nobuhiko; Juteau, Jean-Marc; Cosset, François‐Loïc; Chayama, Kazuaki; Vaillant, Andrew; Liang, T. Jake

doi:10.1053/j.gastro.2009.04.048

Cited by 76 publications

(76 citation statements)

References 44 publications

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“…binding inhibition. This phenomenon could be extended to the inhibition of virus entry, as it has been recently shown that human cytomegalovirus, hepatitis C virus, and HIV entry are blocked by phosphorothioate-modified ODNs, regardless of CpG motifs (33)(34)(35)(36). One could therefore take advantage of this to design antiviral vaccines that target virus entry.…”

Section: Discussionmentioning

confidence: 99%

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

Chiron

Pellat‐Deceunynck

Maillasson

et al. 2009

The Journal of Immunology

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Hypomethylated CpG oligodeoxynucleotides (CpG ODNs) target TLR9 expressed by immune cells and are currently being evaluated as adjuvants in clinical trials. However, TLR signaling can promote some tumor growth and immune evasion, such as in multiple myeloma (MM). Therefore, deciphering the effects of CpG ODNs on cancer cells will help in preventing these adverse effects and in designing future clinical trials. TLR activation induces multiple signaling pathways, notably NF-κB that has been involved in the resistance to TRAIL. Thus, we wondered if CpG ODNs could modulate TRAIL-induced apoptosis in different models of tumors. Here, we show that TLR9+ (NCI-H929, NAN6, KMM1) and TLR9− MM cells (MM1S) were protected by CpG ODNs against recombinant TRAIL-induced apoptosis. By using two fully human, agonist mAbs directed against TRAIL receptors DR4 and DR5 (mapatumumab and lexatumumab, respectively), we show that the protection was restricted to DR5-induced apoptosis. Similar results were observed for two colon cancer (C45 and Colo205) and two breast cancer cell lines (HCC1569 and Cal51). The protection of CpG ODNs was mediated by its nuclease-resistant phosphorothioate backbone independent of TLR9. We next demonstrated by surface plasmon resonance that phosphorothioate-modified CpG ODNs directly bound to either TRAIL or lexatumumab and then decreased their binding to DR5. Finally, NK cell lysis of a DR5-sensitive MM cell line (NCI-H929) through TRAIL was partially inhibited by phosphorothioate-modified CpG ODNs. In conclusion, our results suggest that the phosphorothioate modification of CpG ODNs could dampen the clinical efficacy of CpG ODN-based adjuvants by altering TRAIL/TRAIL receptor interaction.

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Section: Discussionmentioning

confidence: 99%

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

Chiron

Pellat‐Deceunynck

Maillasson

et al. 2009

The Journal of Immunology

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“…Analogous amphipathic interactions may underlie the ability of NAPs to block entry of herpes simplex virus 2 (HSV-2), cytomegalovirus (CMV), and hepatitis C virus (HCV) (16)(17)(18).…”

Section: Uck Hepatitis B Virus (Dhbv) In Its Natural Host the Pekimentioning

confidence: 99%

Nucleic Acid Polymers Prevent the Establishment of Duck Hepatitis B Virus Infection In Vivo

Noordeen

Vaillant²,

Jilbert

2013

Antimicrob Agents Chemother

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c Nucleic acid polymers (NAPs) are novel, broad-spectrum antiviral compounds that use the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) as amphipathic polymers to block amphipathic interactions involved in viral entry. Using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection, NAPs have been shown to have both entry and postentry antiviral activity against DHBV infection in vitro in primary duck hepatocytes (PDH). In the current study, various NAPs were assessed for their prophylactic activity in vivo against DHBV infection in ducks. The degenerate NAP REP 2006 prevented the development of widespread and persistent DHBV infection in 14-day-old ducks, while the acidic-pH-sensitive NAP REP 2031 had little or no prophylactic effect. REP 2006 displayed significant toxicity in ducks, which was attributed to CpG-mediated proinflammation, while REP 2031 (which has no CpG motifs) displayed no toxicity. A third NAP, REP 2055, which was designed to retain amphipathic activity at acidic pH and contained no CpG motifs, was well tolerated and displayed prophylactic activity against DHBV infection at doses as low as 1 mg/kg of body weight/day. These studies suggest that NAPs can be easily and predictably tailored to retain anti-DHBV activity and to have minimal toxic effects in vivo. Future studies are planned to establish the therapeutic efficacy of NAPs against persistent DHBV infection.

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“…The exact mechanisms of these molecules require further investigations. Other compounds such as serum amyloid A [145,146], p7 ion channel-derived peptide H2-3 [147], amphipathic DNA polymers [148], lactoferrins [149], tellimagrandin I and its derivatives [150], indole derivatives [151], and imidazo [1,2α] [1,8]naphthyridine derivatives [152] were found able to inhibit HCV entry with mechanisms that remain to be clarified.…”

Section: Additional Candidate Entry Inhibitorsmentioning

confidence: 99%

Strategies to Preclude Hepatitis C Virus Entry

Burnouf¹,

Lin²

2017

Advances in Treatment of Hepatitis C and B

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Without a preventive vaccine, hepatitis C virus (HCV) remains an important pathogen worldwide with millions of carriers at risk of end-stage liver diseases. Despite the introduction of novel direct-acting antivirals (DAAs), resistance problems, challenges with the difficult-to-treat populations and high costs limit the widespread application of these drugs. Antivirals with alternative mechanism(s) of action, such as by restricting viral entry or cell-to-cell spread, could help expand the scope of antiviral strategies for the management of hepatitis C. Transfusion-associated HCV infection remains another issue in endemic and resource-limited areas around the world. This chapter describes some of the latest developments in antiviral strategies to preclude HCV entry, such as through monoclonal antibodies and small molecules, as well as measures to enhance the safety of therapeutic plasma products in blood transfusion.

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Amphipathic DNA Polymers Inhibit Hepatitis C Virus Infection by Blocking Viral Entry

Abstract: BACKGROUND & AIMS-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.

Cited by 76 publications

References 44 publications

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

Nucleic Acid Polymers Prevent the Establishment of Duck Hepatitis B Virus Infection In Vivo

Strategies to Preclude Hepatitis C Virus Entry

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