Physical Trapping of HIV-1 Synaptic Complex by Different Structural Classes of Integrase Strand Transfer Inhibitors

Raltegravir is an FDA approved inhibitor directed against human immunodeficiency virus type 1 (HIV-1) integrase (IN). In this study, we investigated the mechanisms associated with multiple strand transfer inhibitors capable of inhibiting concerted integration by HIV-1 IN. The results show raltegravi...

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Bibliographic Details
Published in:Biochemistry (Easton) 2010-09, Vol.49 (38), p.8376-8387
Main Authors: Pandey, Krishan K, Bera, Sibes, Vora, Ajaykumar C, Grandgenett, Duane P
Format: Article
Language:English
Subjects:
DNA, Viral - genetics
DNA, Viral - metabolism
DNA, Viral - pharmacology
HIV-1 - genetics
HIV-1 - metabolism
Humans
Integrase Inhibitors - pharmacology
Integrase Inhibitors - therapeutic use
Integrases - genetics
Integrases - pharmacology
Integrases - therapeutic use
Mutation - drug effects
Pyrrolidinones - pharmacology
Quinolones - pharmacology
Raltegravir Potassium
Virus Replication - drug effects
Virus Replication - genetics
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Summary:Raltegravir is an FDA approved inhibitor directed against human immunodeficiency virus type 1 (HIV-1) integrase (IN). In this study, we investigated the mechanisms associated with multiple strand transfer inhibitors capable of inhibiting concerted integration by HIV-1 IN. The results show raltegravir, elvitegravir, MK-2048, RDS 1997, and RDS 2197 all appear to encompass a common inhibitory mechanism by modifying IN−viral DNA interactions. These structurally different inhibitors bind to and inactivate the synaptic complex, an intermediate in the concerted integration pathway in vitro. The inhibitors physically trap the synaptic complex, thereby preventing target DNA binding and thus concerted integration. The efficiency of a particular inhibitor to trap the synaptic complex observed on native agarose gels correlated with its potency for inhibiting the concerted integration reaction, defined by IC50 values for each inhibitor. At low nanomolar concentrations (
ISSN:0006-2960
1520-4995
DOI:10.1021/bi100514s