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Specific inhibitors of HIV capsid assembly binding to the c-terminal domain of the capsid protein: evaluation of 2-arylquinazolines as potential antiviral compounds

Assembly of human immunodeficiency virus (HIV-1) represents an attractive target for antiretroviral therapy which is not exploited by currently available drugs. We established high-throughput screening for assembly inhibitors based on competition of small molecules for the binding of a known dodecap...

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Main Authors: Machara, Aleš (Author) , Lux, Vanda (Author) , Kožíšek, Milan (Author) , Grantz Šašková, Klára (Author) , Štěpánek, Ondřej (Author) , Kotora, Martin (Author) , Parkan, Kamil (Author) , Pávová, Marcela (Author) , Glass, Bärbel (Author) , Sehr, Peter (Author) , Lewis, Joe (Author) , Müller, Barbara (Author) , Kräusslich, Hans-Georg (Author) , Konvalinka, Jan (Author)
Format: Article (Journal)
Language:English
Published: 2016
In: Journal of medicinal chemistry
Year: 2015, Volume: 59, Issue: 2, Pages: 545-558
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5b01089
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acs.jmedchem.5b01089
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Author Notes:Aleš Machara, Vanda Lux, Milan Kožíšek, Klára Grantz Šašková, Ondřej Štěpánek, Martin Kotora, Kamil Parkan, Marcela Pávová, Bärbel Glass, Peter Sehr, Joe Lewis, Barbara Müller, Hans-Georg Kräusslich, and Jan Konvalinka
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Summary:Assembly of human immunodeficiency virus (HIV-1) represents an attractive target for antiretroviral therapy which is not exploited by currently available drugs. We established high-throughput screening for assembly inhibitors based on competition of small molecules for the binding of a known dodecapeptide assembly inhibitor to the C-terminal domain of HIV-1 CA (capsid). Screening of >70000 compounds from different libraries identified 2-arylquinazolines as low micromolecular inhibitors of HIV-1 capsid assembly. We prepared focused libraries of modified 2-arylquinazolines and tested their capacity to bind HIV-1 CA to compete with the known peptide inhibitor and to prevent the replication of HIV-1 in tissue culture. Some of the compounds showed potent binding to the C-terminal domain of CA and were found to block viral replication at low micromolar concentrations.
Item Description:Publication date December 21, 2015
Gesehen am 22.05.2020
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5b01089

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