A Class of Potent Inhibitors of the HIV-1 Nucleocapsid Protein Based on Aminopyrrolic Scaffolds.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
14 May 2020
14 May 2020
Historique:
received:
28
11
2019
accepted:
27
01
2020
entrez:
22
5
2020
pubmed:
22
5
2020
medline:
22
5
2020
Statut:
epublish
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.
Identifiants
pubmed: 32435373
doi: 10.1021/acsmedchemlett.9b00558
pmc: PMC7236033
doi:
Types de publication
Journal Article
Langues
eng
Pagination
698-705Informations de copyright
Copyright © 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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