Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands
It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex c...
Published in: | Bioorganic & Medicinal Chemistry |
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Online Access: | http://hdl.handle.net/11391/1287100 https://doi.org/10.1016/j.bmc.2014.07.018 |
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ftuniperugiairis:oai:research.unipg.it:11391/1287100 2024-04-14T08:10:56+00:00 Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands SANCINETO, LUCA IRACI, NUNZIO BARRECA, MARIA LETIZIA MASSARI, SERENA MANFRONI, GIUSEPPE CECCHETTI, Violetta TABARRINI, Oriana Gianmarco Corazza Alessandro Marcello Dirk Daelemans Christophe Pannecouque Sancineto, Luca Iraci, Nunzio Barreca, MARIA LETIZIA Massari, Serena Manfroni, Giuseppe Gianmarco, Corazza Cecchetti, Violetta Alessandro, Marcello Dirk, Daeleman Christophe, Pannecouque Tabarrini, Oriana 2014 STAMPA http://hdl.handle.net/11391/1287100 https://doi.org/10.1016/j.bmc.2014.07.018 eng eng info:eu-repo/semantics/altIdentifier/pmid/25127466 info:eu-repo/semantics/altIdentifier/wos/WOS:000341293300015 volume:22 issue:17 firstpage:4658 lastpage:4666 numberofpages:9 journal:BIOORGANIC & MEDICINAL CHEMISTRY http://hdl.handle.net/11391/1287100 doi:10.1016/j.bmc.2014.07.018 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84906934907 DML 6-desfluoroquinolone RT Transactivation Anti-HIV compounds info:eu-repo/semantics/article 2014 ftuniperugiairis https://doi.org/10.1016/j.bmc.2014.07.018 2024-03-21T15:50:13Z It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT–RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives. Article in Journal/Newspaper DML IRIS Università degli Studi di Perugia Bioorganic & Medicinal Chemistry 22 17 4658 4666 |
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Open Polar |
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IRIS Università degli Studi di Perugia |
op_collection_id |
ftuniperugiairis |
language |
English |
topic |
DML 6-desfluoroquinolone RT Transactivation Anti-HIV compounds |
spellingShingle |
DML 6-desfluoroquinolone RT Transactivation Anti-HIV compounds SANCINETO, LUCA IRACI, NUNZIO BARRECA, MARIA LETIZIA MASSARI, SERENA MANFRONI, GIUSEPPE CECCHETTI, Violetta TABARRINI, Oriana Gianmarco Corazza Alessandro Marcello Dirk Daelemans Christophe Pannecouque Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
topic_facet |
DML 6-desfluoroquinolone RT Transactivation Anti-HIV compounds |
description |
It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT–RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives. |
author2 |
Sancineto, Luca Iraci, Nunzio Barreca, MARIA LETIZIA Massari, Serena Manfroni, Giuseppe Gianmarco, Corazza Cecchetti, Violetta Alessandro, Marcello Dirk, Daeleman Christophe, Pannecouque Tabarrini, Oriana |
format |
Article in Journal/Newspaper |
author |
SANCINETO, LUCA IRACI, NUNZIO BARRECA, MARIA LETIZIA MASSARI, SERENA MANFRONI, GIUSEPPE CECCHETTI, Violetta TABARRINI, Oriana Gianmarco Corazza Alessandro Marcello Dirk Daelemans Christophe Pannecouque |
author_facet |
SANCINETO, LUCA IRACI, NUNZIO BARRECA, MARIA LETIZIA MASSARI, SERENA MANFRONI, GIUSEPPE CECCHETTI, Violetta TABARRINI, Oriana Gianmarco Corazza Alessandro Marcello Dirk Daelemans Christophe Pannecouque |
author_sort |
SANCINETO, LUCA |
title |
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
title_short |
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
title_full |
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
title_fullStr |
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
title_full_unstemmed |
Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands |
title_sort |
exploiting the anti-hiv 6-desfluoroquinolones to design multiple ligands |
publishDate |
2014 |
url |
http://hdl.handle.net/11391/1287100 https://doi.org/10.1016/j.bmc.2014.07.018 |
genre |
DML |
genre_facet |
DML |
op_relation |
info:eu-repo/semantics/altIdentifier/pmid/25127466 info:eu-repo/semantics/altIdentifier/wos/WOS:000341293300015 volume:22 issue:17 firstpage:4658 lastpage:4666 numberofpages:9 journal:BIOORGANIC & MEDICINAL CHEMISTRY http://hdl.handle.net/11391/1287100 doi:10.1016/j.bmc.2014.07.018 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84906934907 |
op_doi |
https://doi.org/10.1016/j.bmc.2014.07.018 |
container_title |
Bioorganic & Medicinal Chemistry |
container_volume |
22 |
container_issue |
17 |
container_start_page |
4658 |
op_container_end_page |
4666 |
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1796308595993739264 |