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
  • 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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