title: Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation.
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.
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Martini
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, KU Leuven, 3000, Leuven, Flanders, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, KU Leuven, 3000, Leuven, Flanders, Belgium.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrarese
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Cabiddu
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.
authors.forename: Elisa Rita
authors.initials: ER
authors.lastname: Ceresola
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcaterra
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iovine
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.|Department of Department of Biotechnology and Life Sciences, University of Insubria, via Ravasi 2, 21100, Varese, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Canducci
authors.affiliation: Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy. botta.maurizio@gmail.com.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy. tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D002460:Cell Line; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D044947:Flavonolignans / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D062105:Molecular Docking Simulation; D031625:Morus / Q000737:chemistry / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D014779:Virus Replication / Q000187:drug effects
chemical_list: D005419:Flavonoids; D044947:Flavonolignans; D019428:HIV Integrase Inhibitors; D011994:Recombinant Proteins; C000611437:kuwanon-L; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: HIV-1 integrase; allosterism; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions