Structural and Inhibition Studies of the RNase H Function of XMRV RT

[Jemal]

This is new I think.

Structural and Inhibition Studies of the RNase H Function of XMRV Reverse Transcriptase

Karen A. Kirby1,2, Bruno Marchand1,2, Yee Tsuey Ong1,2, Tanyaradzwa P. Ndongwe1,2, Atsuko Hachiya1,2, Eleftherios Michailidis1,2, Maxwell D. Leslie1,2, Daniel V. Sietsema1,2, Tracy L. Fetterly1,2, Christopher A. Dorst1,2, Kamalendra Singh1,2, Zhengqiang Wang3, Michael A. Parniak4 and Stefan G. Sarafianos1,2,5,*

First published January 2012

Ribonuclease H (RNase H) inhibitors (RNHIs) have gained attention as potential HIV-1 therapeutics. Although several RNHIs have been studied in the context of HIV-1 Reverse Transcriptase (RT) RNase H, there is no information on inhibitors that might affect the RNase H activity of other RTs. We performed biochemical, virological, crystallographic, and molecular modeling studies to compare the RNase H function and inhibition profiles of the gammaretroviral Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and Moloney Murine Leukemia Virus (MoMLV) RTs to HIV-1 RT. The RNase H activity of XMRV RT is significantly lower than HIV-1 RT and comparable to MoMLV RT. XMRV and MoMLV, but not HIV-1 RT, had optimal RNase H activities in the presence of Mn2+ and not Mg2+. Using hydroxyl-radical foot-printing assays we demonstrated that the distance between the polymerase and RNase H domains in MoMLV and XMRV RTs is longer than in HIV-1 RT by ?3.4 . We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with IC50s ranging from ?0.8 to 0.02 ?M. Two acylhydrazones effective against HIV-1 RT RNase H were less potent against the XMRV enzyme. We also solved the crystal structure of an XMRV RNase H fragment at high resolution (1.5 ) and determined the molecular details of the XMRV RNase H active site, thus providing a framework that would be useful for the design of antivirals that target RNase H.

http://aac.asm.org/content/early/2012/01/10/AAC.06000-11.abstract

 

[Overstressed]

Hi Jemal,

Rnase H is very interesting, indeed. In that context you might want to read about the oligonucleotide of Prof.Dr. Karin Moelling. She discovered Rnase H, and developed a oligonucleotide which activates the Rnase H. This way HIV thinks it needs to transcribe it's RNA to DNA. With this, HIV destroys it's own blue-print, or commits suicide.

I find the work of Prof. Dr. Karin Moelling very interesting, it's a shame she doesn't get any funding for the development of this oligonucleotide to make it into clinical trials.

OS.