ArticleMolecular pharmacology2009
An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 50 citations in OpenAlex.
- 2-(Trihydroxyphenyl)thienopyrimidinones as Key Scaffolds for Targeting a Novel Allosteric Site of HIV-1 Integrase.Molecules (Basel, Switzerland) · 2025Article
- Brief Histories of Retroviral Integration Research and Associated International Conferences.Viruses · 2024Review
- 5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action.Frontiers in cellular and infection microbiology · 2023Article
- Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis.eLife · 2020Article
- Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis.Viruses · 2020Review
- Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition.The Journal of biological chemistry · 2019Review
- A Ligand-Based Virtual Screening Method Using Direct Quantification of Generalization Ability.Molecules (Basel, Switzerland) · 2019Article
- Nuclear landscape of HIV-1 infection and integration.Nature reviews. Microbiology · 2017Review
- Different Pathways Leading to Integrase Inhibitors Resistance.Frontiers in microbiology · 2016Review
- Methods for the Analyses of Inhibitor-Induced Aberrant Multimerization of HIV-1 Integrase.Methods in molecular biology (Clifton, N.J.) · 2016Article
- HIV-1 integrase multimerization as a therapeutic target.Current topics in microbiology and immunology · 2015Review
- The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase.Retrovirology · 2014Article
- A new class of multimerization selective inhibitors of HIV-1 integrase.PLoS pathogens · 2014Article
- Inhibiting the HIV integration process: past, present, and the future.Journal of medicinal chemistry · 2014Article
- Allosteric modulation of protein oligomerization: an emerging approach to drug design.Frontiers in chemistry · 2014Review
- Molecular modeling study on the allosteric inhibition mechanism of HIV-1 integrase by LEDGF/p75 binding site inhibitors.PloS one · 2014Article
- Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors.Expert reviews in molecular medicine · 2013Review
- Allosteric inhibition of HIV-1 integrase activity.Current opinion in chemical biology · 2013Review
- The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors.The Journal of biological chemistry · 2013Article
- Architecture and assembly of HIV integrase multimers in the absence of DNA substrates.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
HIV-1 integrase (IN) is a validated target for developing antiretroviral inhibitors. Using affinity acetylation and mass spectrometric (MS) analysis, we previously identified a tetra-acetylated inhibitor (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N-[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propenyl]-L-serine methyl ester; compound 1] that selectively modified Lys173 at the IN dimer interface. Here we extend our efforts to dissect the mechanism of inhibition and structural features that are important for the selective binding of compound 1. Using a subunit exchange assay, we found that the inhibitor strongly modulates dynamic interactions between IN subunits. Restricting such interactions does not directly interfere with IN binding to DNA substrates or cellular cofactor lens epithelium-derived growth factor, but it compromises the formation of the fully functional nucleoprotein complex. Studies comparing compound 1 with a structurally related IN inhibitor, the tetra-acetylated-chicoric acid derivative (2R,3R)-2,3-bis[[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propen-1-yl]oxy]-butanedioic acid (compound 2), indicated striking mechanistic differences between these agents. The structures of the two inhibitors differ only in their central linker regions, with compounds 1 and 2 containing a single methyl ester group and two carboxylic acids, respectively. MS experiments highlighted the importance of these structural differences for selective binding of compound 1 to the IN dimer interface. Moreover, molecular modeling of compound 1 complexed to IN identified a potential inhibitor binding cavity and provided structural clues regarding a possible role of the central methyl ester group in establishing an extensive hydrogen bonding network with both interacting subunits. The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN.
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Registered trials
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