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

Francesca Esposito, Cristina Tintori, Riccardo Martini, Frauke Christ, Zeger Debyser, Roberto Ferrarese, Gianluigi Cabiddu, Angela Corona, Elisa Rita Ceresola, Andrea Calcaterra, Valentina Iovine, Bruno Botta, Massimo Clementi, Filippo Canducci, Maurizio Botta, Enzo Tramontano

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2507-2512
Number of pages6
JournalChemBioChem
Volume16
Issue number17
DOIs
Publication statusPublished - Nov 23 2015

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Keywords

  • allosterism
  • HIV-1 integrase
  • inhibitors
  • integrase multimerization
  • kuwanon-L
  • protein-protein interactions

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

Cite this

Esposito, F., Tintori, C., Martini, R., Christ, F., Debyser, Z., Ferrarese, R., Cabiddu, G., Corona, A., Ceresola, E. R., Calcaterra, A., Iovine, V., Botta, B., Clementi, M., Canducci, F., Botta, M., & Tramontano, E. (2015). Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation. ChemBioChem, 16(17), 2507-2512. https://doi.org/10.1002/cbic.201500385