NDLI: Allosteric Inhibition of Human Immunodeficiency Virus Integrase LATE BLOCK DURING VIRAL REPLICATION AND ABNORMAL MULTIMERIZATION INVOLVING SPECIFIC PROTEIN DOMAINS

Content Provider	Journal of Biological Chemistry (JBC)
Author	Gupta, Kushol Brady, Troy Dyer, Benjamin M. Malani, Nirav Hwang, Young Male, Frances Nolte, Robert T. Wang, Liping Velthuisen, Emile Jeffrey, Jerry Duyne, Gregory D. Van Bushman, Frederic D.
Abstract	HIV-1 replication in the presence of antiviral agents results in evolution of drug-resistant variants, motivating the search for additional drug classes. Here we report studies of GSK1264, which was identified as a compound that disrupts the interaction between HIV-1 integrase (IN) and the cellular factor lens epithelium-derived growth factor (LEDGF)/p75. GSK1264 displayed potent antiviral activity and was found to bind at the site occupied by LEDGF/p75 on IN by x-ray crystallography. Assays of HIV replication in the presence of GSK1264 showed only modest inhibition of the early infection steps and little effect on integration targeting, which is guided by the LEDGF/p75·IN interaction. In contrast, inhibition of late replication steps was more potent. Particle production was normal, but particles showed reduced infectivity. GSK1264 promoted aggregation of IN and preformed LEDGF/p75·IN complexes, suggesting a mechanism of inhibition. LEDGF/p75 was not displaced from IN during aggregation, indicating trapping of LEDGF/p75 in aggregates. Aggregation assays with truncated IN variants revealed that a construct with catalytic and C-terminal domains of IN only formed an open polymer associated with efficient drug-induced aggregation. These data suggest that the allosteric inhibitors of IN are promising antiviral agents and provide new information on their mechanism of action.
Related Links	http://www.jbc.org/content/289/30/20477.abstract
Ending Page	20488
Starting Page	20477
Page Count	12
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	30
Volume Number	289
DOI	10.1074/jbc.M114.551119
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-07-25
Access Restriction	Open
Subject Keyword	Bioinformatics Biophysics Genomics Retrovirus X-ray Crystallography Analytical Ultracentrifugation (AUC) Oligomerization Size Exclusion Chromatography In-line with Multiangle Light Scattering (SEC-MALS) Small Angle X-ray Scattering (SAXS) Time-resolved FRET Enzymology
Alternative Title	Allosteric Inhibition of Human Immunodeficiency Virus Integrase
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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