New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

被引：137

作者：

Tsiang, Manuel ^{[1
]}

Jones, Gregg S. ^{[1
]}

Niedziela-Majka, Anita ^{[1
]}

Kan, Elaine ^{[1
]}

Lansdon, Eric B. ^{[1
]}

Huang, Wayne ^{[1
]}

Hung, Magdeleine ^{[1
]}

Samuel, Dharmaraj ^{[1
]}

Novikov, Nikolai ^{[1
]}

Xu, Yili ^{[1
]}

Mitchell, Michael ^{[1
]}

Guo, Hongyan ^{[1
]}

Babaoglu, Kerim ^{[1
]}

Liu, Xiaohong ^{[1
]}

Geleziunas, Romas ^{[1
]}

Sakowicz, Roman ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 25期

关键词：

VIRUS TYPE-1 INTEGRASE; SMALL-MOLECULE INHIBITORS; DNA-BINDING DOMAIN; PEPTIDE INHIBITORS; VIRAL-DNA; IN-VITRO; LEDGF/P75; DISCOVERY; REVEALS; PROTEIN;

D O I：

10.1074/jbc.M112.347534

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV-1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF.LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction.

引用

页码：21189 / 21203

页数：15

共 64 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].