(Thia)calixarenephosphonic acids as potent inhibitors of the nucleic acid chaperone activity of the HIV-1 nucleocapsid protein with a new binding mode and multi-target antiviral activity.
Fiche publication
Date publication
février 2020
Journal
ACS infectious diseases
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah, Pr MELY Yves, Mr HUMBERT Nicolas
Tous les auteurs :
Humbert N, Kovalenko L, Saladini F, Giannini A, Pires M, Botzanowski T, Cherenok S, Boudier C, Sharma KK, Real E, Zaporozhets OA, Cianférani S, Seguin-Devaux C, Poggialini F, Botta M, Zazzi M, Kalchenko VI, Mori M, Mély Y
Lien Pubmed
Résumé
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 sub-micromolar 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 form thus a class of noncovalent NC inhibitors, endowed with a new binding mode and multi-target antiviral activity.
Référence
ACS Infect Dis. 2020 Feb 11;: