2. Academic Validation
  3. Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

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

  • Chembiochem. 2015 Nov;16(17):2507-12. doi: 10.1002/cbic.201500385.
Francesca Esposito 1,  Cristina Tintori 2,  Riccardo Martini 2,  Frauke Christ 3,  Zeger Debyser 3,  Roberto Ferrarese 4,  Gianluigi Cabiddu 1,  Angela Corona 1,  Elisa Rita Ceresola 4,  Andrea Calcaterra 5,  Valentina Iovine 5,  Bruno Botta 5,  Massimo Clementi 4,  Filippo Canducci 4 6,  Maurizio Botta 7,  Enzo Tramontano 8
Affiliations

Affiliations

  • 1 Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy.
  • 2 Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy.
  • 3 Laboratory for Molecular Virology and Gene Therapy, KU Leuven, 3000, Leuven, Flanders, Belgium.
  • 4 Laboratory of Virology, San Raffaele Hospital, IRCCS, via Olgettina 60, 20132, Milano, Italy.
  • 5 Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
  • 6 Department of Department of Biotechnology and Life Sciences, University of Insubria, via Ravasi 2, 21100, Varese, Italy.
  • 7 Department of Biotechnologies, Chemical and Pharmacy, University of Siena, via Alcide de Gasperi 2, 53100, Siena, Italy. [email protected].
  • 8 Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS 554, 09042, Monserrato, Cagliari, Italy. [email protected].
PMID: 26360521 DOI: 10.1002/cbic.201500385
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.

Keywords

HIV-1 integrase; allosterism; inhibitors; integrase multimerization; kuwanon-L; protein-protein interactions.

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