Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds

0458499 - ÚOCHB 2017 RIV US eng J - Journal Article
Machara, A. - Lux, V. - Kožíšek, Milan - Grantz Šašková, Klára - Štěpánek, O. - Kotora, M. - Parkan, Kamil - Pávová, Marcela - Glass, B. - Sehr, P. - Lewis, J. - Müller, B. - Kräusslich, H. G. - Konvalinka, Jan
Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds.
Journal of Medicinal Chemistry. Roč. 59, č. 2 (2016), s. 545-558. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GA13-19561S
EU Projects: European Commission(XE) 201095 - HIV ACE
Institutional support: RVO:61388963
Keywords : HIV-1 assembly * capsid * high-throughput screening * AlphaScreen assay
Subject RIV: CE - Biochemistry
Impact factor: 6.259, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0258765