Abstract
BackgroundNonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 Å from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs.ResultsUsing a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs.ConclusionsThe antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0244-2) contains supplementary material, which is available to authorized users.
Highlights
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 Å from the polymerase active site
The NNRTI resistant double mutant K103N/Y181C caused a substantial decrease in susceptibility to RPV analogs 6, 8, 9, 13, 21, and 27, whereas this mutant caused a minor loss in susceptibility to RPV, 7, 11, and 13 (
Because several of our RPV analogs were active against the first set of NNRTI resistant mutants, we tested the antiviral activities of RPV and the most promising analogs 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 21, 26, and 27 against a much broader panel of resistant mutants
Summary
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 Å from the polymerase active site. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs. HIV-1 reverse transcriptase (RT) is a target for many drugs used in highly active antiretroviral therapy (HAART) to treat HIV-1 infections [1]. As yet, no drugs that target the RNase H of HIV-1 RT, there are two classes of drugs that target the DNA polymerase. While NNRTIs effectively block the replication of WT HIV-1, NNRTI-resistant mutants can emerge during treatment, many of which cause cross-resistance among the approved NNRTIs
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