Considerations for structure-based drug design targeting HIV-1 reverse transcriptase

© Springer Science+Business Media Dordrecht 2015 HIV-1 reverse transcriptase (RT) copies the viral single-stranded RNAgenome into a double-stranded DNA version, and is a central target for anti-AIDStherapeutics. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleosideinhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have beendetermined in complexes with substrates and/or inhibitors, and the structures haverevealed different conformational and functional states of the enzyme. Rilpivirineand etravirine, two NNRTI drugs with high potency against common resistantvariants, were discovered and developed through a multidisciplinary structure-baseddrug design effort. The resilience of rilpivirine and etravirine to resistance mutationsresults from the structural flexibility and compactness of these drugs. Recentinsights into mechanisms of inhibition by the allosteric NNRTIs include (i) dynamicsliding of RT/NNRTI complexes along template-primers and (ii) displacement of theRT primer grip that repositions the 30-primer terminus away from the polymeraseactive site.