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Silencing of viral RNAs by small double-stranded siDNA
Retrovirologyvolume 6, Article number: P58 (2009)
We are developing an alternative approach to siRNA, which may be designated as siDNA, small interfering DNA, by using hairpin-loop-structured DNA oligodeoxynucleotides (ODN), targeted to viral or cellular mRNAs. ODNs activate the viral RNase H in retroviral particles and cellular RNases H inside the cell. Also Ago2 may play a role. Other inhibitory mechanisms such as translational arrest may contribute.
We selected ODNs against various viral and mRNAs of HIV [1–3], HSV , Influenza , HCV, HBV, and telomerase RNA in malignant melanoma cells in mice . The ODNs were applied with or without carriers. Furthermore their effects were directly compared to those of single-stranded antisense DNAs and siRNAs to allow comparison of the various efficiencies. The ODNs were most effective in HIV. We are able to induce HIV suicide , inactivate HIV virus particles to prevent infections, inactivate cell-free HIV in the blood from infected individuals , in the vagina of mice , and increase survival time of retroviral-infected mice . Also influenza virus replication was reduced in the lungs of a mouse model. Furthermore we could reduce malignant melanoma-formation targeting the telomerase. The effects are sequence- and dose-dependent, but the optimal algorithm is not yet known. We are analyzing whether there is a preference for G tracts, which may form higher-ordered structures. The dsODNs are often superior to single-stranded antisense DNA and resemble the effects of siRNAs  but with different kinetics. The method may complement existing silencing approaches.
Jendis J, Strack B, Moelling K: Inhibition of replication of drug-resistant HIV type 1 isolates by polypurine tract-specific oligodeoxynucleotideTFO A. AIDS Res Hum Retroviruses. 1998, 14: 999-1005. 10.1089/aid.1998.14.999.
Jendis J, Strack B, Volkmann S, Boni J, Moelling K: Inhibition of replication of fresh HIV type 1 patient isolates by a polypurine tract-specific self-complementary oligodeoxy-nucleotide. AIDS Res Hum Retroviruses. 1996, 12: 1161-1168. 10.1089/aid.1996.12.1161.
Moelling K, Abels S, Jendis J, Matskevich A, Heinrich J: Silencing of HIV by hairpin-loop-structured DNA oligonucleotide. FEBS Lett. 2006, 580: 3545-3550. 10.1016/j.febslet.2006.05.033.
Falkenhagen A, Heinrich J, Moelling K: Short hairpin-loop-structured Oligodeoxynucleotides reduce HSV-1 Replication. Virol J. 2009, 6: 43-10.1186/1743-422X-6-43.
Kwok T, Helfer H, Alam MI, Heinrich J, Pavlovic J, Moelling K: Inhibition of influenza A virus replication by short double-stranded oligodeoxynucleotides. Arch Virol. 2009, 154: 109-114. 10.1007/s00705-008-0262-z.
Noreen F, Heinrich J, Moelling K: Antitumor activity of small double-stranded oligodeoxynucleotides targeting telomerase RNA in malignant melanoma cells. Oligonucleotides. 2009, 19: 169-178. 10.1089/oli.2008.0170.
Matskevich AA, Ziogas A, Heinrich J, Quast S, Moelling K: Short partially double-stranded oligodeoxynucleotide induces reverse transcriptase-mediated cleavage of HIV RNA and abrogates infectivity of virions. AIDS Res Hum Retroviruses. 2006, 22: 1220-1230. 10.1089/aid.2006.22.1220.
Heinrich J, Mathur S, Matskevich AA, Moelling K: Oligonucleotide-mediated retroviral RNase H activation leads to reduced HIV-1 titer in patient-derived plasma. AIDS. 2009, 23: 213-221. 10.1097/QAD.0b013e32831c5480.
Wittmer-Elzaouk L, Jung-Shiu J, Heinrich J, Moelling K: Retroviral self-inactivation in the mouse vagina induced by short DNA. Antiviral Res. 2009, 82: 22-28. 10.1016/j.antiviral.2009.01.002.
Matzen K, Elzaouk L, Matskevich A, Nitzsche A, Heinrich J, Moelling K: RNase H-induced suicide of a retrovirus by oligodeoxy-nucleotides in a mouse model. Nat Biotechnol. 2007, 25: 669-674. 10.1038/nbt1311.
Moelling K, Matskevich A, Jung JS: Relationship between Retroviral Replication and RNA Interference Machineries. Cold Spring Harb Symp Quant Biol. 2006, 71: 365-368. 10.1101/sqb.2006.71.010.