Conformational inhibitors of the HIV-1 Rev response element identified through a FRET-based screening approach

The complex formed between the HIV-1 protein Rev and the Rev Response Element (RRE) in the genomic RNA of the virus represents an attractive target for antiretroviral therapy. To date, however, there are no RRE-Rev inhibitors in clinical use. In this study we have applied a fluorescence resonance energy transfer (FRET) assay based on placing Cy3- and Cy5-labeled oligomeric probes at distal domain locations within the RRE to identify small-molecule compounds capable of perturbing the spatial organization of RRE domains and disrupting the association of Rev monomers. After screening a library of bioactive compounds and approved drugs, we identified two molecules, myricetin and raloxifene, that recognize the RRE and inhibit the RRE-Rev interaction in vitro and in cellulo. Both compounds exhibited antiretroviral activity with favorable selectivity indexes, and further analyses involving RRE mutants suggested that myricetin modulated the conformation of the RRE through binding to a four-helix intersection. Collectively, these findings provide proof of concept for targeting the RRE-Rev complex and identify myricetin and raloxifene as promising starting points for the development of novel anti-HIV agents.

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Publication Details

Journal
Communications Chemistry
Published
2026-11-06
DOI
https://doi.org/10.1038/s42004-026-02272-4
Primary Topic
HIV/AIDS drug development and treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Conformational inhibitors of the HIV-1 Rev response element identified through a FRET-based screening approach

José Gallego, Manuela Beltrán, Maria Carmen Puertas, Luis Miguel Bedoya et al.
1 links
Communications Chemistry
HIV/AIDS drug development and treatment
article

Conformational inhibitors of the HIV-1 Rev response element identified through a FRET-based screening approach

José Gallego, Manuela Beltrán, Maria Carmen Puertas, Luis Miguel Bedoya, Vicente Marchán, Sara Morón‐López, Jon Izquierdo-Pujol, Mateusz P Szewczyk, Sergi Chumillas, José Alcamı́, Javier Martínez‐Picado, Saurabh Loharch, Clara Devesa-Ibarreche
article en

Abstract

The complex formed between the HIV-1 protein Rev and the Rev Response Element (RRE) in the genomic RNA of the virus represents an attractive target for antiretroviral therapy. To date, however, there are no RRE-Rev inhibitors in clinical use. In this study we have applied a fluorescence resonance energy transfer (FRET) assay based on placing Cy3- and Cy5-labeled oligomeric probes at distal domain locations within the RRE to identify small-molecule compounds capable of perturbing the spatial organization of RRE domains and disrupting the association of Rev monomers. After screening a library of bioactive compounds and approved drugs, we identified two molecules, myricetin and raloxifene, that recognize the RRE and inhibit the RRE-Rev interaction in vitro and in cellulo. Both compounds exhibited antiretroviral activity with favorable selectivity indexes, and further analyses involving RRE mutants suggested that myricetin modulated the conformation of the RRE through binding to a four-helix intersection. Collectively, these findings provide proof of concept for targeting the RRE-Rev complex and identify myricetin and raloxifene as promising starting points for the development of novel anti-HIV agents.

Communications Chemistry
Universitat de Vic - Universitat Central de Catalunya (ES), Institució Catalana de Recerca i Estudis Avançats (ES), Universidad Complutense de Madrid (ES), Instituto de Salud Carlos III (ES), Valencia Catholic University Saint Vincent Martyr (ES), IrsiCaixa (ES), Centro Nacional de Microbiologia (ES), Hospital Clínic de Barcelona (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Institut de Biomedicina de la Universitat de Barcelona (ES), Centro de Investigación Biomédica en Red Enfermedades Infecciosas (ES), Universitat de Barcelona (ES)
Gilead Sciences, Centres de Recerca de Catalunya, Gilead Research Scholars, Generalitat de Catalunya, Generalitat Valenciana, National Institutes of Health, European Regional Development Fund, Agencia Estatal de Investigación, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 14%
HIV/AIDS drug development and treatment
DOIOpen Access PDFOpenAlex
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