ArticleThe Journal of biological chemistry2018
Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 citations in OpenAlex.
- Targeting Human Immunodeficiency Virus Integrase Beyond the Active Site: The Discovery and Development of Allosteric Integrase Inhibitors.ChemMedChem · 2026Review
- Mapping the TAR vRNA Interaction with HIV-1 Integrase.Viruses · 2026Article
- Mapping the vRNA Interaction with HIV-1 Integrase.bioRxiv : the preprint server for biology · 2026Article
- Cutting-edge developments in computer-aided anti-HIV drug design.Frontiers in immunology · 2026Review
- Review
- Optimizing the Multimerization Properties of Quinoline-Based Allosteric HIV-1 Integrase Inhibitors.Viruses · 2024Review
- The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario.International journal of molecular sciences · 2023Review
- Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase.Antimicrobial agents and chemotherapy · 2023Article
- Evaluation of a flavonoid library for inhibition of interaction of HIV-1 integrase with human LEDGF/p75 towards a structure-activity relationship.Annals of medicine · 2022Article
- Article
- Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric Integrase Inhibitor.ACS medicinal chemistry letters · 2022Article
- Multimodal Functionalities of HIV-1 Integrase.Viruses · 2022Review
- Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602.Journal of virology · 2022Article
- Structure and function of retroviral integrase.Nature reviews. Microbiology · 2022Review
- HIV-1 integrase binding to genomic RNA 5'-UTR induces local structural changes in vitro and in virio.Retrovirology · 2021Article
- A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site.PLoS pathogens · 2021Article
- Computational design of small molecular modulators of protein-protein interactions with a novel thermodynamic cycle: Allosteric inhibitors of HIV-1 integrase.Protein science : a publication of the Protein Society · 2021Article
- Classification and Design of HIV-1 Integrase Inhibitors Based on Machine Learning.Computational and mathematical methods in medicine · 2021Article
- 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
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Authors and funding
19 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recently, a new class of HIV-1 integrase (IN) inhibitors with a dual mode of action, called IN-LEDGF/p75 allosteric inhibitors (INLAIs), was described. Designed to interfere with the IN-LEDGF/p75 interaction during viral integration, unexpectedly, their major impact was on virus maturation. This activity has been linked to induction of aberrant IN multimerization, whereas inhibition of the IN-LEDGF/p75 interaction accounts for weaker antiretroviral effect at integration. Because these dual activities result from INLAI binding to IN at a single binding site, we expected that these activities co-evolved together, driven by the affinity for IN. Using an original INLAI, MUT-A, and its activity on an Ala-125 (A125) IN variant, we found that these two activities on A125-IN can be fully dissociated: MUT-A-induced IN multimerization and the formation of eccentric condensates in viral particles, which are responsible for inhibition of virus maturation, were lost, whereas inhibition of the IN-LEDGF/p75 interaction and consequently integration was fully retained. Hence, the mere binding of INLAI to A125 IN is insufficient to promote the conformational changes of IN required for aberrant multimerization. By analyzing the X-ray structures of MUT-A bound to the IN catalytic core domain (CCD) with or without the Ala-125 polymorphism, we discovered that the loss of IN multimerization is due to stabilization of the A125-IN variant CCD dimer, highlighting the importance of the CCD dimerization energy for IN multimerization. Our study reveals that affinity for the LEDGF/p75-binding pocket is not sufficient to induce INLAI-dependent IN multimerization and the associated inhibition of viral maturation.
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