TITLE

Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication

AUTHOR(S)
Christ, Frauke; Voet, Arnout; Marchand, Arnaud; Nicolet, Stefan; Desimmie, Belete A.; Marchand, Damien; Bardiot, Dorothée; Van der Veken, Nam Joo; Van Remoortel, Barbara; Strelkov, Sergei V; De Maeyer, Marc; Chaltin, Patrick; Debyser, Zeger
PUB. DATE
June 2010
SOURCE
Nature Chemical Biology;Jun2010, Vol. 6 Issue 6, p442
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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-Å 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.
ACCESSION #
50522992

 

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