Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor

Author(s)
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
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.

Organisation(s)
Department of Pharmaceutical Chemistry
Journal
ChemBioChem: a european journal of chemical biology
Volume
16
Pages
2507-12
No. of pages
6
ISSN
1439-4227
DOI
https://doi.org/10.1002/cbic.201500385
Publication date
11-2015
Publication status
Published
Peer reviewed
Yes
Austrian Fields of Science 2012
301207 Pharmaceutical chemistry
Keywords
Allosteric Regulation, Binding Sites, Cell Line, Flavonoids/chemistry, Flavonolignans/chemistry, HIV Integrase/chemistry, HIV Integrase Inhibitors/chemistry, HIV-1/physiology, Humans, Molecular Docking Simulation, Morus/chemistry, Plant Roots/chemistry, Protein Structure, Tertiary, Recombinant Proteins/biosynthesis, Virus Replication/drug effects
Portal url
https://ucris.univie.ac.at/portal/en/publications/kuwanonl-as-a-new-allosteric-hiv1-integrase-inhibitor(76a7fefc-eb7d-414c-8984-80f334e9c19f).html