Journal article
Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid
Journal of virology, v 86(16), pp 8472-8481
Aug 2012
PMID: 22647699
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4′-[dibenzo[
b,d
]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CA-specific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity.
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Details
- Title
- Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid
- Creators
- Sandhya Kortagere - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USANavid Madani - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USAMarie K Mankowski - Department of Infectious Disease Research, Southern Research Institute, Frederick, Maryland, USAArne Schön - Department of Biology, The Johns Hopkins University, Baltimore, Maryland, USAIsaac Zentner - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAGokul Swaminathan - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAAmy Princiotto - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USAKevin Anthony - USA IBT Bioservices, Maryland, USAApara Oza - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USALuz-Jeannette Sierra - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAShendra R Passic - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAXiaozhao Wang - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USADavid M Jones - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USAEric Stavale - USA IBT Bioservices, Maryland, USAFred C Krebs - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAJulio Martín-García - Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAErnesto Freire - Department of Biology, The Johns Hopkins University, Baltimore, Maryland, USARoger G Ptak - Department of Infectious Disease Research, Southern Research Institute, Frederick, Maryland, USAJoseph Sodroski - Department of Infectious Disease Research, Southern Research Institute, Frederick, Maryland, USASimon Cocklin - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USAAmos B Smith - Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Publication Details
- Journal of virology, v 86(16), pp 8472-8481
- Publisher
- American Society for Microbiology; 1752 N St., N.W., Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology
- Web of Science ID
- WOS:000307198300013
- Scopus ID
- 2-s2.0-84865063652
- Other Identifier
- 991014878192604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Virology