A Novel Drug Binding Site in HIV-1 Reverse Transcriptase Responsible for Perturbing its RNase H Activity
Drug resistance constitutes one of the major challenges in current anti-HIV therapy. Identifying new small molecule (or RNA) candidates that bind HIV-reverse transcriptase (RT) in unique ways would help uncover novel drug target sites and aid in the fight against HIV. Now a study in ACS Chemical Biology reports the crystal structure of HIV-1 reverse transcriptase (RT) complexed with dihydroxy benzoyl naphthyl hydrazone (DHBNH), an HIV-1 RT RNase H inhibitor. This small molecule binds to the p66 kDa subunit of HIV-1 RT at a novel site in close proximity to the polymerase active site and the non-nucleoside RT inhibitor hydrophobic binding pocket. This molecular interaction may cause a conformational perturbation that makes the RNA strand of a substrate RNA.DNA hybrid duplex inaccessible to the RNase H catalytic cleavage site. The findings of this work are significant for developing novel HIV-1 inhibitors that target both the polymerase and RNase H activities.
To see the full report: ACS Chemical Biology (2006) 1, 702-712.
