Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutantsReportar como inadecuado

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, 13:11

First Online: 16 February 2016Received: 09 December 2015Accepted: 05 February 2016


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.

KeywordsHIV-1 Nonnucleoside reverse transcriptase inhibitors Rilpivirine Antiviral activity Resistance Analogs Susceptibility Binding pocket Doravirine Electronic supplementary materialThe online version of this article doi:10.1186-s12977-016-0244-2 contains supplementary material, which is available to authorized users.

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