Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds
详细信息 查看全文
- 作者：Ale? Machara ; Vanda Lux ; Milan Ko?í?ek ; Klára Grantz ?a?ková ; Ond?ej ?těpánek ; Martin Kotora ; Kamil Parkan ; Marcela Pávová ; B?rbel Glass ; Peter Sehr ; Joe Lewis ; Barbara Müller ; Hans-Georg Kr?usslich ; Jan Konvalinka
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 28, 2016
- 年：2016
- 卷：59
- 期：2
- 页码：545-558
- 全文大小：587K
- ISSN：1520-4804
文摘
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.