Uncovering the complexities of retroviral ribonuclease H reveals its potential as a therapeutic target.
Successful long-term management of HIV infection will require targeted inhibition of multiple steps essential for virus replication. Currently, both nucleoside- and nonnucleoside-based inhibitors of DNA polymerase function, in combination with antagonists of HIV protease, have been shown to be clinically beneficial. However, it is clear that RNase H activity of the multifunctional HIV-1 reverse transcriptase (RT) is absolutely required for completion of retroviral DNA synthesis, thereby rendering this function an attractive target for drug development. Although generally viewed as a sequence-independent activity, highly precise RNase H cleavage is required in order to remove the RNA primers of (-) and (+) strand DNA synthesis (a host-derived tRNA and the polypurine tract, respectively), thereby preserving the ends of linear DNA and facilitating integration. The availability of highly purified, recombinant RT/RNase H has allowed a thorough dissection of these multiple events and their potential for therapeutic intervention. Our current understanding of retroviral RNase H function and the status of small molecule inhibitors are the focus of this review.
Klarmann
George J
GJ
Reverse Transcriptase Biochemistry Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, P.O. Box B Frederick, MD 21702, USA.
Hawkins
Mary E
ME
Le Grice
Stuart F J
SF
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D012313:RNA / Q000378:metabolism; D016914:Ribonuclease H / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D012313:RNA; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H