(Thia)calixarenephosphonic Acids as Potent Inhibitors of the Nucleic Acid Chaperone Activity of the HIV-1 Nucleocapsid Protein with a New Binding Mode and Multitarget Antiviral ActivityClick to copy article linkArticle link copied!
- Nicolas HumbertNicolas HumbertLaboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceMore by Nicolas Humbert
- Lesia KovalenkoLesia KovalenkoLaboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceDepartment of Chemistry, Taras Shevchenko National University of Kyiv, 01601 Kyiv, UkraineMore by Lesia Kovalenko
- Francesco SaladiniFrancesco SaladiniDepartment of Medical Biotechnologies, University of Siena, viale Mario Bracci no. 16, 53100 Siena, ItalyMore by Francesco Saladini
- Alessia GianniniAlessia GianniniDepartment of Medical Biotechnologies, University of Siena, viale Mario Bracci no. 16, 53100 Siena, ItalyMore by Alessia Giannini
- Manuel PiresManuel PiresLaboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceMore by Manuel Pires
- Thomas BotzanowskiThomas BotzanowskiLaboratoire de Spectrométrie de Masse BioOrganique, IPHC UMR 7178 CNRS, Université de Strasbourg, 67000 Strasbourg, FranceMore by Thomas Botzanowski
- Sergiy CherenokSergiy CherenokInstitute of Organic Chemistry, National Academy of Science of Ukraine, Murmanska str. 5, Kyiv 02660, UkraineMore by Sergiy Cherenok
- Christian BoudierChristian BoudierLaboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceMore by Christian Boudier
- Kamal K. SharmaKamal K. SharmaLaboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceMore by Kamal K. Sharma
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- Olga A. ZaporozhetsOlga A. ZaporozhetsDepartment of Chemistry, Taras Shevchenko National University of Kyiv, 01601 Kyiv, UkraineMore by Olga A. Zaporozhets
- Sarah CianféraniSarah CianféraniLaboratoire de Spectrométrie de Masse BioOrganique, IPHC UMR 7178 CNRS, Université de Strasbourg, 67000 Strasbourg, FranceMore by Sarah Cianférani
- Carole Seguin-DevauxCarole Seguin-DevauxDepartment of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, LuxembourgMore by Carole Seguin-Devaux
- Federica PoggialiniFederica PoggialiniDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 Università degli Studi di Siena, via Aldo Moro 2, I-53019 Siena, ItalyMore by Federica Poggialini
- Maurizio BottaMaurizio BottaDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 Università degli Studi di Siena, via Aldo Moro 2, I-53019 Siena, ItalyMore by Maurizio Botta
- Maurizio ZazziMaurizio ZazziDepartment of Medical Biotechnologies, University of Siena, viale Mario Bracci no. 16, 53100 Siena, ItalyMore by Maurizio Zazzi
- Vitaly I. KalchenkoVitaly I. KalchenkoInstitute of Organic Chemistry, National Academy of Science of Ukraine, Murmanska str. 5, Kyiv 02660, UkraineMore by Vitaly I. Kalchenko
- Mattia MoriMattia MoriDepartment of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 Università degli Studi di Siena, via Aldo Moro 2, I-53019 Siena, ItalyMore by Mattia Mori
- Yves Mély*Yves Mély*Tel: +33 (0)3 68 85 42 63. Fax: +33 (0)3 68 85 43 13. Email: [email protected]Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, FranceMore by Yves Mély
Abstract
The nucleocapsid protein (NC) is a highly conserved protein that plays key roles in HIV-1 replication through its nucleic acid chaperone properties mediated by its two zinc fingers and basic residues. NC is a promising target for antiviral therapy, particularly to control viral strains resistant to currently available drugs. Since calixarenes with antiviral properties have been described, we explored the ability of calixarene hydroxymethylphosphonic or sulfonic acids to inhibit NC chaperone properties and exhibit antiviral activity. By using fluorescence-based assays, we selected four calixarenes inhibiting NC chaperone activity with submicromolar IC50 values. These compounds were further shown by mass spectrometry, isothermal titration calorimetry, and fluorescence anisotropy to bind NC with no zinc ejection and to compete with nucleic acids for the binding to NC. Molecular dynamic simulations further indicated that these compounds interact via their phosphonate or sulfonate groups with the basic surface of NC but not with the hydrophobic plateau at the top of the folded fingers. Cellular studies showed that the most soluble compound CIP201 inhibited the infectivity of wild-type and drug-resistant HIV-1 strains at low micromolar concentrations, primarily targeting the early steps of HIV-1 replication. Moreover, CIP201 was also found to inhibit the flipping and polymerization activity of reverse transcriptase. Calixarenes thus form a class of noncovalent NC inhibitors, endowed with a new binding mode and multitarget antiviral activity.
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