3p1g

Publication Abstract from PubMed

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 Mn(2+) and not Mg(2+). 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 approximately 3.4 A. We identified one naphthyridinone and one hydroxyisoquinolinedione as potent inhibitors of HIV-1 and XMRV RT RNases H with IC(50)s ranging from approximately 0.8 to 0.02 muM. 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 A) 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.

Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase.,Kirby KA, Marchand B, Ong YT, Ndongwe TP, Hachiya A, Michailidis E, Leslie MD, Sietsema DV, Fetterly TL, Dorst CA, Singh K, Wang Z, Parniak MA, Sarafianos SG Antimicrob Agents Chemother. 2012 Jan 17. PMID:22252812^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.