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.

Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

CERESOLA, ELISA RITA;CANDUCCI, FILIPPO;
2015-01-01

Abstract

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.
2015
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1439-7633
allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; 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
Esposito, Francesca; Tintori, Cristina; Martini, Riccardo; Christ, Frauke; Debyser, Zeger; Ferrarese, Roberto; Cabiddu, Gianluigi; Corona, Angela; Cer...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2057939
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