Considerations for Structure-Based Drug Design Targeting HIV-1 Reverse Transcriptase

HIV-1 reverse transcriptase (RT) copies the viral single-stranded RNA genome into a double-stranded DNA version, and is a central target for anti-AIDS therapeutics. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have revealed different conformational and functional states of the enzyme. Rilpivirine and etravirine, two NNRTI drugs with high potency against common resistant variants, were discovered and developed through a multidisciplinary structure-based drug design effort. The resilience of rilpivirine and etravirine to resistance mutations results from the structural flexibility and compactness of these drugs. Recent insights into mechanisms of inhibition by the allosteric NNRTIs include (i) dynamic sliding of RT/NNRTI complexes along template-primers and (ii) displacement of the RT primer grip that repositions the 3'-primer terminus away from the polymerase active site.