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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

In vitro resistance development for RO-0335, a novel diphenylether nonnucleoside reverse transcriptase inhibitor.

H Javanbakht1, R G Ptak, E Chow

  • 1Virology Disease Biology Area, Roche Palo Alto, Palo Alto, CA 94304-1396, USA. hassan.javanbakht@roche.com

Antiviral Research
|March 12, 2010
PubMed
Summary

Novel diphenylether nonnucleoside reverse transcriptase inhibitors (NNRTIs) show resistance pathways. Mutations V106I/A plus F227C or V106I/Y188L confer reduced susceptibility to RO-0335, impacting HIV-1 treatment.

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Last Updated: Jun 15, 2026

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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Area of Science:

  • Virology
  • Medicinal Chemistry
  • Drug Resistance

Background:

  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are crucial in HIV-1 therapy.
  • First-generation NNRTIs like efavirenz and nevirapine face challenges due to resistance, cross-resistance, and side effects.
  • Novel NNRTIs are needed to overcome limitations of existing treatments.

Purpose of the Study:

  • To investigate resistance development pathways against the novel diphenylether NNRTI, RO-0335.
  • To identify specific mutations conferring reduced susceptibility to RO-0335.
  • To assess the fitness of resistant HIV-1 variants.

Main Methods:

  • Sequential passage experiments at low multiplicity of infection (MOI) to select for resistance mutations.
  • Site-directed mutagenesis to characterize the impact of observed mutations.
  • Fitness evaluation of selected resistant mutations compared to wild-type HIV-1.

Main Results:

  • Two distinct resistance pathways emerged, characterized by mutations at V106I/A plus F227C or V106I/Y188L.
  • Multiple mutations were generally required for significant loss of susceptibility, except for Y188L.
  • Resistant variants with F227C or quadruple mutations exhibited lower relative fitness than wild-type HIV-1.

Conclusions:

  • The diphenylether NNRTI RO-0335 selects for specific resistance mutations in HIV-1.
  • Understanding these resistance pathways is vital for developing effective HIV-1 therapies.
  • The observed fitness costs may influence the evolutionary trajectory of resistant viral strains.