Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation
| Autor: | Riccardo Martini, Elisa Rita Ceresola, Bruno Botta, Massimo Clementi, Enzo Tramontano, Andrea Calcaterra, Cristina Tintori, Frauke Christ, Gianluigi Cabiddu, Filippo Canducci, Francesca Esposito, Valentina Iovine, Maurizio Botta, Roberto Ferrarese, Zeger Debyser, Angela Corona |
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| Přispěvatelé: | Esposito, F., Tintori, C., Martini, R., Christ, F., Debyser, Z., Ferrarese, R., Cabiddu, G., Corona, A., Ceresola, E. R., Calcaterra, A., Iovine, V., Botta, B., Clementi, M., Canducci, F., Botta, M., Tramontano, E. |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Protein Structure
Allosteric regulation protein-protein interactions allosterism HIV-1 integrase inhibitors integrase multimerization kuwanon-L Allosteric Regulation Binding Sites Cell Line Flavonoids Flavonolignans HIV Integrase HIV Integrase Inhibitors HIV-1 Humans Molecular Docking Simulation Morus Plant Roots Protein Structure Tertiary Recombinant Proteins Virus Replication Biochemistry Organic Chemistry Molecular Medicine Molecular Biology Biology Protein–protein interaction Binding site Virtual screening Active site Integrase Docking (molecular) biology.protein biochemistry organic chemistry molecular medicine molecular biology Tertiary |
| Popis: | HIV-1 integrase (IN) active site inhibitors are the latest class of drugs approved for HIV treatment. The selection of IN strand-transfer drug-resistant HIV strains in patients supports the development of new agents that are active as allosteric IN inhibitors. Here, a docking-based virtual screening has been applied to a small library of natural ligands to identify new allosteric IN inhibitors that target the sucrose binding pocket. From theoretical studies, kuwanon-L emerged as the most promising binder and was thus selected for biological studies. Biochemical studies showed that kuwanon-L is able to inhibit the HIV-1 IN catalytic activity in the absence and in the presence of LEDGF/p75 protein, the IN dimerization, and the IN/LEDGF binding. Kuwanon-L also inhibited HIV-1 replication in cell cultures. Overall, docking and biochemical results suggest that kuwanon-L binds to an allosteric binding pocket and can be considered an attractive lead for the development of new allosteric IN antiviral agents. Docking simulations exploring a small library of natural compounds, together with biological studies, allowed kuwanon-L to be identified as a new HIV-1 integrase (IN) inhibitor with an allosteric mode of action. Kuwanon-L can thus be considered an attractive lead for the development of new allosteric IN antiviral agents. |
| Databáze: | OpenAIRE |
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