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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered noncompetitive inhibitors that structurally alter reverse transcriptase (RT) and dramatically decrease catalysis. In this report, biochemical analysis with various divalent cations was used to demonstrate that NNRTIs and divalent cation-dNTP complexes are mutually exclusive, inhibiting each other's binding to RT/primer/template (RT-P/T) complexes. The binding of catalytically competent divalent cation-dNTP complexes to RT-P/T was measured with Mg 2+ , Mn 2+ , Zn 2+ , Co 2+ , and Ni 2+ using Ca 2+ , a noncatalytic cation, for displacement. Binding strength order was Mn 2+ ≈ Zn 2+ ≫ Co 2+ &gt; Mg 2+ ≈ Ni 2+ . Consistent with but not exclusive to mutually exclusive binding, primer extension assays showed that stronger divalent cation-dNTP complexes were more resistant to NNRTIs (efavirenz (EFV), rilpivirine (RPV), and nevirapine (NVP)). Filtration assays demonstrated that divalent cation-dNTP complexes inhibited the binding of 14 C-labeled EFV to RT-P/T with stronger binding complexes formed with Mn 2+ inhibiting more potently than those with Mg 2+ . Conversely, filter binding assays demonstrated that EFV inhibited 3 H-labeled dNTP binding to RT-P/T complexes with displacement of Mn 2+ -dNTP complexes requiring much greater concentrations of EFV than the more weakly bound Mg 2+ -dNTP complexes. EFV bound relatively weakly to the NNRTI resistant K103N RT; but, binding was modestly enhanced in the presence of P/T, and EFV was easily displaced by divalent cation-dNTP complexes. This suggests that K103N overcomes EFV inhibition mostly by binding more weakly to the drug and is in contrast to other reports that indicate K103N has little to no effect on drug or dNTP binding. Overall, this biochemical analysis supports recent biophysical analyses of NNRTI-RT interactions that indicate mutually exclusive binding.

biochemistry

Non-nucleoside Reverse Transcriptase Inhibitors Inhibit Reverse Transcriptase through a Mutually Exclusive Interaction with Divalent Cation–dNTP Complexes