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 language | English |
|---|---|
| Pages (from-to) | 2507-2512 |
| Number of pages | 6 |
| Journal | ChemBioChem |
| Volume | 16 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - 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
Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor : Molecular Modeling and Biological Evaluation. / Esposito, Francesca; Tintori, Cristina; Martini, Riccardo; Christ, Frauke; Debyser, Zeger; Ferrarese, Roberto; Cabiddu, Gianluigi; Corona, Angela; Ceresola, Elisa Rita; Calcaterra, Andrea; Iovine, Valentina; Botta, Bruno; Clementi, Massimo; Canducci, Filippo; Botta, Maurizio; Tramontano, Enzo.
In: ChemBioChem, Vol. 16, No. 17, 23.11.2015, p. 2507-2512.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Kuwanon-L as a New Allosteric HIV-1 Integrase Inhibitor
T2 - Molecular Modeling and Biological Evaluation
AU - Esposito, Francesca
AU - Tintori, Cristina
AU - Martini, Riccardo
AU - Christ, Frauke
AU - Debyser, Zeger
AU - Ferrarese, Roberto
AU - Cabiddu, Gianluigi
AU - Corona, Angela
AU - Ceresola, Elisa Rita
AU - Calcaterra, Andrea
AU - Iovine, Valentina
AU - Botta, Bruno
AU - Clementi, Massimo
AU - Canducci, Filippo
AU - Botta, Maurizio
AU - Tramontano, Enzo
PY - 2015/11/23
Y1 - 2015/11/23
N2 - 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.
AB - 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.
KW - allosterism
KW - HIV-1 integrase
KW - inhibitors
KW - integrase multimerization
KW - kuwanon-L
KW - protein-protein interactions
UR - http://www.scopus.com/inward/record.url?scp=84954369076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954369076&partnerID=8YFLogxK
U2 - 10.1002/cbic.201500385
DO - 10.1002/cbic.201500385
M3 - Article
AN - SCOPUS:84954369076
VL - 16
SP - 2507
EP - 2512
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 17
ER -