title: Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Charles University , 128 43 Prague 2, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Machara
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg , Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Vanda
authors.initials: V
authors.lastname: Lux
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Kožíšek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.|Department of Biochemistry, Faculty of Science, Charles University , 128 43 Prague 2, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Grantz Šašková
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Charles University , 128 43 Prague 2, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Štěpánek
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Charles University , 128 43 Prague 2, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Kotora
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Parkan
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg , Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.|Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Marcela
authors.initials: M
authors.lastname: Pávová
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg , Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Glass
authors.affiliation: Chemical Biology Core Facility, European Molecular Biology Laboratory , 691 17 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sehr
authors.affiliation: Chemical Biology Core Facility, European Molecular Biology Laboratory , 691 17 Heidelberg, Germany.
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg , Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Müller
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg , Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kräusslich
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center , Flemingovo n. 2, 166 10 Prague 6, Czech Republic.|Department of Biochemistry, Faculty of Science, Charles University , 128 43 Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015203:Reproducibility of Results; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D011799:Quinazolines; D011994:Recombinant Proteins; D054852:Small Molecule Libraries