Journal
NATURE CHEMICAL BIOLOGY
Volume 6, Issue 6, Pages 442-448Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.370
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Funding
- Flemish Agentschap voor Innovatie door Wetenschap en Technologie [60813]
- FWO [G.0530.08]
- EC [THINC (HEALTH-F3-2008-201032)]
- Research Fund
- K.U. Leuven
- Science and Technology in Flanders
- Industrieel Onderzoeksfonds mandate
- Bijzonder Onderzoeksfonds-PhD scholarship
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Lens epithelium-derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase that promotes viral integration by tethering the preintegration complex to the chromatin. By virtue of its crucial role in the early steps of HIV replication, the interaction between LEDGF/p75 and integrase represents an attractive target for antiviral therapy. We have rationally designed a series of 2-(quinolin-3-yl) acetic acid derivatives (LEDGINs) that act as potent inhibitors of the LEDGF/p75-integrase interaction and HIV-1 replication at submicromolar concentration by blocking the integration step. A 1.84-angstrom resolution crystal structure corroborates the binding of the inhibitor in the LEDGF/p75-binding pocket of integrase. Together with the lack of cross-resistance with two clinical integrase inhibitors, these findings define the 2-(quinolin-3-yl) acetic acid derivatives as the first genuine allosteric HIV-1 integrase inhibitors. Our work demonstrates the feasibility of rational design of small molecules inhibiting the protein-protein interaction between a viral protein and a cellular host factor.
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