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Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs

Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of be...

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Autores principales: Chumillas, Sergi, Loharch, Saurabh, Beltrán, Manuela, Szewczyk, Mateusz P., Bernal, Silvia, Puertas, Maria C., Martinez-Picado, Javier, Alcamí, José, Bedoya, Luis M., Marchán, Vicente, Gallego, José
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609163/
https://www.ncbi.nlm.nih.gov/pubmed/37894510
http://dx.doi.org/10.3390/molecules28207031
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author Chumillas, Sergi
Loharch, Saurabh
Beltrán, Manuela
Szewczyk, Mateusz P.
Bernal, Silvia
Puertas, Maria C.
Martinez-Picado, Javier
Alcamí, José
Bedoya, Luis M.
Marchán, Vicente
Gallego, José
author_facet Chumillas, Sergi
Loharch, Saurabh
Beltrán, Manuela
Szewczyk, Mateusz P.
Bernal, Silvia
Puertas, Maria C.
Martinez-Picado, Javier
Alcamí, José
Bedoya, Luis M.
Marchán, Vicente
Gallego, José
author_sort Chumillas, Sergi
collection PubMed
description Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE–Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE–Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE–Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function.
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spelling pubmed-106091632023-10-28 Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs Chumillas, Sergi Loharch, Saurabh Beltrán, Manuela Szewczyk, Mateusz P. Bernal, Silvia Puertas, Maria C. Martinez-Picado, Javier Alcamí, José Bedoya, Luis M. Marchán, Vicente Gallego, José Molecules Article Human immunodeficiency virus-type 1 (HIV-1) remains one of the leading contributors to the global burden of disease, and novel antiretroviral agents with alternative mechanisms are needed to cure this infection. Here, we describe an exploratory attempt to optimize the antiretroviral properties of benfluron, a cytostatic agent previously reported to exhibit strong anti-HIV activity likely based on inhibitory actions on virus transcription and Rev-mediated viral RNA export. After obtaining six analogs designed to modify the benzo[c]fluorenone system of the parent molecule, we examined their antiretroviral and toxicity properties together with their capacity to recognize the Rev Recognition Element (RRE) of the virus RNA and inhibit the RRE–Rev interaction. The results indicated that both the benzo[c] and cyclopentanone components of benfluron are required for strong RRE–Rev target engagement and antiretroviral activity and revealed the relative impact of these moieties on RRE affinity, RRE–Rev inhibition, antiviral action and cellular toxicity. These data provide insights into the biological properties of the benzo[c]fluorenone scaffold and contribute to facilitating the design of new anti-HIV agents based on the inhibition of Rev function. MDPI 2023-10-11 /pmc/articles/PMC10609163/ /pubmed/37894510 http://dx.doi.org/10.3390/molecules28207031 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chumillas, Sergi
Loharch, Saurabh
Beltrán, Manuela
Szewczyk, Mateusz P.
Bernal, Silvia
Puertas, Maria C.
Martinez-Picado, Javier
Alcamí, José
Bedoya, Luis M.
Marchán, Vicente
Gallego, José
Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title_full Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title_fullStr Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title_full_unstemmed Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title_short Exploring the HIV-1 Rev Recognition Element (RRE)–Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs
title_sort exploring the hiv-1 rev recognition element (rre)–rev inhibitory capacity and antiretroviral action of benfluron analogs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10609163/
https://www.ncbi.nlm.nih.gov/pubmed/37894510
http://dx.doi.org/10.3390/molecules28207031
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