Ribonuclease H domain of HIV-1 reverse transcriptase (HIV-1 RNase H)

The HIV-1 RNase H domain is a critical enzymatic component of the reverse transcriptase (RT) protein, located at the C-terminus of the p66 subunit (NIH, 2012). Its primary biological function is to catalyze the endonucleolytic cleavage of the RNA strand within the RNA/DNA heteroduplex intermediate formed during the reverse transcription of the viral genome (UniProt, 2024). This activity is essential for the synthesis of double-stranded viral DNA, as it facilitates the removal of the RNA template, the excision of the tRNA primer, and the processing of the polypurine tract (PPT) to initiate plus-strand DNA synthesis (Wikipedia, 2024). Despite its essential role in the viral life cycle and its potential as a therapeutic target, there are currently no FDA-approved drugs that specifically target the RNase H domain; most existing RT inhibitors target the polymerase domain (PubMed, 2021). Drug discovery efforts face significant challenges, including the relatively flat topography of the RNase H active site and the high degree of structural similarity with human RNase H1, which raises concerns about potential off-target toxicity (NIH, 2015). Experimental inhibitors, such as beta-thujaplicinol and various diketo acids, typically work by chelating the divalent metal ions required for the domain's catalytic activity (PubMed, 2022). Targeting this domain is particularly attractive for overcoming resistance to current antiretroviral therapies, as mutations in the RNase H domain are distinct from those in the polymerase domain (PubMed, 2021).

Other names

HIV-1 RT RNase H domainRibonuclease H domain of p66HIV-1 reverse transcriptase RNase HRetroviral ribonuclease H

Inhibition of RNase H activity by chelating divalent metal ions (Mg2+ or Mn2+) in the active site (DEDD motif) or through allosteric inhibition, thereby blocking the degradation of the viral RNA template and halting reverse transcription.