A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants

Abstract

BackgroundThe recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1.ResultsWe used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective.ConclusionsSubtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.

Study on Anti-Hiv Activity of Diarylaniline Derivatives Using Quantitative Structure-Activity Relationship (Qsar)

“…In Table 5, descriptor qO7 always appears in all of the models, indicating the important descriptor in anti-HIV activity of DAAN derivatives. This result is in a good agreement with Johnson et al [19] showing DAAN derivatives bind to reverse transcriptase by hydrogen bonding. Model 1, model 2, and model 3 have higher r 2 -value than model 4, but their PRESS-value were significantly higher than model 4.…”

Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants

“…These mutants were chosen because they have been selected in patients and are well distributed around the NNRTI binding pocket [1, 2]. In previous work, RPV potently inhibited infection of both the WT and the mutant viruses with IC 50 values of 0.24 ± 0.1 nM and <2 nM, respectively [20]. DOR potently inhibited the replication of the WT HIV-1 vector in the single-cycle assay (0.67 ± 0.14 nM) and L100I mutant (1.14 ± 0.2 nM) as shown in (Fig.…”

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

“…Unlike K103N and Y181C, the mutations K101P and Y181I/V require at least two base changes to be made and therefore are likely more difficult to develop. In addition, the accumulation of multiple NNRTI resistance mutations, as occurs in treatment-experienced HIV-1 ϩ individuals, can enhance RPV resistance (20,55,64,65), which is less likely to occur prior to therapy or to be transmitted to newly infected individuals (66). Thus, it appears that isolates that are highly resistant to RPV are difficult to develop compared to mutants that arise during use of other NNRTIs, such as EFV and NVP.…”