A Class of Potent Inhibitors of the HIV-1 Nucleocapsid Protein Based on Aminopyrrolic Scaffolds.

Autor:	Ciaco S; Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France.; Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 Università degli Studi di Siena, via Aldo Moro 2, I-53019 Siena, Italy., Humbert N; Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France., Real E; Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France., Boudier C; Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France., Francesconi O; Dipartimento di Chimica 'Ugo Schiff' and INSTM, University of Florence, via della Lastruccia, 3-13, 50019 Sesto Fiorentino, Florence, Italy., Roelens S; Dipartimento di Chimica 'Ugo Schiff' and INSTM, University of Florence, via della Lastruccia, 3-13, 50019 Sesto Fiorentino, Florence, Italy., Nativi C; Dipartimento di Chimica 'Ugo Schiff' and INSTM, University of Florence, via della Lastruccia, 3-13, 50019 Sesto Fiorentino, Florence, Italy., Seguin-Devaux C; Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg., Mori M; Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 Università degli Studi di Siena, via Aldo Moro 2, I-53019 Siena, Italy., Mély Y; Laboratoire de Bioimagerie et Pathologies, UMR 7021 CNRS, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Jan 27; Vol. 11 (5), pp. 698-705. Date of Electronic Publication: 2020 Jan 27 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.9b00558
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (Copyright © 2020 American Chemical Society.)
Databáze:	MEDLINE
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