Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains

被引:14
|
作者
Mori, Mattia [1 ]
Kovalenko, Lesia [2 ,3 ]
Malancona, Savina [4 ]
Saladini, Francesco [5 ]
De Forni, Davide [6 ]
Pires, Manuel [2 ]
Humbert, Nicolas [2 ]
Real, Eleonore [2 ]
Botzanowski, Thomas [7 ]
Cianferani, Sarah [7 ]
Giannini, Alessia [5 ]
Dasso Lang, Maria Chiara [1 ]
Cugia, Giulia [6 ]
Poddesu, Barbara [6 ]
Lori, Franco [6 ]
Zazzi, Maurizio [5 ]
Harper, Steven [4 ]
Summa, Vincenzo [4 ]
Mely, Yves [2 ]
Botta, Maurizio [1 ,8 ]
机构
[1] Univ Siena, Dept Biotechnol Chem & Pharm, Via Aldo Moro 2, I-53100 Siena, Italy
[2] Univ Strasbourg, Lab Biophoton & Pharmacol, UMR 7213, Fac Pharm,CNRS, 74 Route Rhin, F-67401 Illkirch Graffenstaden, France
[3] Kyiv Natl Taras Shevchenko Univ, Dept Chem, UA-01033 Kiev, Ukraine
[4] IRBM Sci Pk SpA, Via Pontina Km 30-600, I-00071 Pomezia, RM, Italy
[5] Univ Siena, Dept Med Biotechnol, Viale Mario Bracci 16, I-50100 Siena, Italy
[6] ViroStatics Srl, Viale Umberto 1 46, I-07100 Sassari, Italy
[7] Univ Strasbourg, CNRS, Lab Spectrometrie Masse BioOrgan, IPHC UMR 7178, F-67000 Strasbourg, France
[8] Temple Univ, Sbarro Inst Canc Res & Mol Med, Coll Sci & Technol, Ctr Biotechnol, BioLife Sci Bldg,Suite 333,1900 N 12th St, Philadelphia, PA 19122 USA
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; ACID-CHAPERONE ACTIVITY; POTENTIAL BIOACTIVATION MECHANISM; ZINC-FINGER STRUCTURES; MINUS-STRAND TRANSFER; NORDIHYDROGUAIARETIC ACID; REVERSE TRANSCRIPTION; ANTI-HIV; QUINONE METHIDES; DNA-SYNTHESIS;
D O I
10.1021/acschembio.7b00907
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:253 / 266
页数:14
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