ArticleRetrovirology2012
A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
Article in Retrovirology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 34 citations in OpenAlex.
- Scaffold hopping yields novel furo[3,2-Acta pharmaceutica Sinica. B · 2026Article
- Identification of Novel Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors by Exploring the Primer Grip Region.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Avoiding Drug Resistance in HIV Reverse Transcriptase.Chemical reviews · 2021Review
- Structure-based non-nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants.Chemical biology & drug design · 2021Article
- Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs.Journal of virology · 2019Article
- The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.Journal of medicinal chemistry · 2019Article
- An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors.Bioorganic & medicinal chemistry · 2017Article
- Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants.Journal of acquired immune deficiency syndromes (1999) · 2016Article
- Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants.Retrovirology · 2016Article
- Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase.Antimicrobial agents and chemotherapy · 2015Article
- Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.Memorias do Instituto Oswaldo Cruz · 2015Review
- Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance.ACS medicinal chemistry letters · 2015Article
- Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.Journal of medicinal chemistry · 2015Article
- Review
- Integrated computational tools for identification of CCR5 antagonists as potential HIV-1 entry inhibitors: homology modeling, virtual screening, molecular dynamics simulations and 3D QSAR analysis.Molecules (Basel, Switzerland) · 2014Article
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
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.
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