Download MendeleyRational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication.
Christ, F., Voet, A., Marchand, A., Nicolet, S., Desimmie, B.A., Marchand, D., Bardiot, D., Van der Veken, N.J., Van Remoortel, B., Strelkov, S.V., De Maeyer, M., Chaltin, P., Debyser, Z.(2010) Nat Chem Biol 6: 442-448
- PubMed: 20473303
- DOI: https://doi.org/10.1038/nchembio.370
- Primary Citation of Related Structures:
3LPT, 3LPU - PubMed Abstract:
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-A 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.
Organizational Affiliation:
Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium.
