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.

Kuwanon-L as a new allosteric HIV-1 integrase inhibitor: molecular modeling and biological evaluation / Esposito, Francesca; Tintori, Cristina; Martini, Riccardo; Christ, Frauke; Debyser, Zeger; Ferrarese, Roberto; Cabiddu, Gianluigi; Corona, Angela; Ceresola, Elisa Rita; Calcaterra, Andrea; Iovine, Valentina; Botta, Bruno; Clementi, Massimo; Canducci, Filippo; Botta, Maurizio; Tramontano, Enzo. - In: CHEMBIOCHEM. - ISSN 1439-4227. - STAMPA. - 16:17(2015), pp. 2507-2512. [10.1002/cbic.201500385]

Kuwanon-L as a new allosteric HIV-1 integrase inhibitor: molecular modeling and biological evaluation

CALCATERRA, ANDREA;IOVINE, VALENTINA;BOTTA, Bruno;
2015

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.
allosterism; HIV-1 integrase; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions; biochemistry; organic chemistry; molecular medicine; molecular biology
01 Pubblicazione su rivista::01a Articolo in rivista
Kuwanon-L as a new allosteric HIV-1 integrase inhibitor: molecular modeling and biological evaluation / Esposito, Francesca; Tintori, Cristina; Martini, Riccardo; Christ, Frauke; Debyser, Zeger; Ferrarese, Roberto; Cabiddu, Gianluigi; Corona, Angela; Ceresola, Elisa Rita; Calcaterra, Andrea; Iovine, Valentina; Botta, Bruno; Clementi, Massimo; Canducci, Filippo; Botta, Maurizio; Tramontano, Enzo. - In: CHEMBIOCHEM. - ISSN 1439-4227. - STAMPA. - 16:17(2015), pp. 2507-2512. [10.1002/cbic.201500385]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/961962
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