Targeting the retroviral ribonuclease H by rational drug design

Ribonucleases H or RNases H are conserved and exist in almost every organism. They generate and remove RNA primers, which are required for DNA replication. RNases H hydrolyze RNA in RNA-DNA hybrids. RNases H and related enzymes contribute to reduction of gene expression in antisense and small-interfering RNA mechanisms for gene silencing. Retroviruses code for RNases H, which are required for DNA provirus synthesis. Their RNase H is fused to the reverse transcriptase and essential for virus replication inside the cell. Retroviruses code for four enzymes, three of which have been targeted by antiretroviral therapies. A drug against the fourth one, the retroviral RNase H, does not yet exist. The viral but not cellular RNases H should be targeted by drug design. Some details will be discussed here. Furthermore, a compound is described, which enables the RNase H to kill cell-free HIV particles by driving the virus into suicide - with potential use as a microbicide. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins