Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains.
Fiche publication
Date publication
janvier 2018
Journal
ACS chemical biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah, Pr MELY Yves, Mr HUMBERT Nicolas
Tous les auteurs :
Mori M, Kovalenko L, Malancona S, Saladini F, De Forni D, Pires M, Humbert N, Real E, Botzanowski T, Cianférani S, Giannini A, Dasso Lang MC, Cugia G, Poddesu B, Lori F, Zazzi M, Harper S, Summa V, Mely Y, Botta M
Lien Pubmed
Résumé
HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR. Here, using a multidisciplinary approach combining in silico screening, fluorescence-based molecular assays, and cellular antiviral assays, we identified nordihydroguaiaretic acid (6), as a novel natural product inhibitor of NC. By using NMR, mass spectrometry, fluorescence spectroscopy, and molecular modeling, 6 was found to act through a dual mechanism of action never highlighted before for NC inhibitors (NCIs). First, the molecule recognizes and binds NC noncovalently, which results in the inhibition of the nucleic acid chaperone properties of NC. In a second step, chemical oxidation of 6 induces a potent chemical inactivation of the protein. Overall, 6 inhibits NC and the replication of wild-type and drug-resistant HIV-1 strains in the low micromolar range with moderate cytotoxicity that makes it a profitable tool compound as well as a good starting point for the development of pharmacologically relevant NCIs.
Mots clés
Anti-HIV Agents, chemistry, Apoptosis, drug effects, Drug Evaluation, Preclinical, methods, Drug Resistance, Viral, drug effects, HIV-1, drug effects, Humans, Inhibitory Concentration 50, Leukocytes, Mononuclear, drug effects, Magnetic Resonance Spectroscopy, Mitochondria, drug effects, Models, Molecular, Nucleocapsid Proteins, antagonists & inhibitors, Spectrometry, Fluorescence, Structure-Activity Relationship, Virus Replication, drug effects
Référence
ACS Chem. Biol.. 2018 01 19;13(1):253-266