Fiche publication
Date publication
mai 2020
Journal
ACS medicinal chemistry letters
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MELY Yves
,
Mr HUMBERT Nicolas
Tous les auteurs :
Ciaco S, Humbert N, Real E, Boudier C, Francesconi O, Roelens S, Nativi C, Seguin-Devaux C, Mori M, Mély Y
Lien Pubmed
Résumé
The HIV-1 nucleocapsid protein 7 (NC) is a potential target for effective antiretroviral therapy due to its central role in virus replication, mainly linked to nucleic acid (NA) chaperone activity, and low susceptibility to drug resistance. By screening a compounds library, we identified the aminopyrrolic compound CN14_17, a known carbohydrate binding agent, that inhibits the NC chaperone activity in the low micromolar range. Different from most of available NC inhibitors, CN14_17 fully prevents the NC-induced annealing of complementary NA sequences. Using fluorescence assays and isothermal titration calorimetry, we found that CN14_17 competes with NC for the binding to NAs, preferentially targeting single-stranded sequences. Molecular dynamics simulations confirmed that binding to cTAR occurs preferably within the guanosine-rich single stranded sequence. Finally, CN14_17 exhibited antiretroviral activity in the low micromolar range, although with a moderate therapeutic index. Overall, CN14_17 might be the progenitor of a new promising class of NC inhibitors.
Référence
ACS Med Chem Lett. 2020 May 14;11(5):698-705
