title: Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication.
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.
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Arnout
authors.initials: A
authors.lastname: Voet
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchand
authors.forename: Stefan
authors.initials: S
authors.lastname: Nicolet
authors.forename: Belete A
authors.initials: BA
authors.lastname: Desimmie
authors.forename: Damien
authors.initials: D
authors.lastname: Marchand
authors.forename: Dorothée
authors.initials: D
authors.lastname: Bardiot
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Van der Veken
authors.forename: Barbara
authors.initials: B
authors.lastname: Van Remoortel
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Strelkov
authors.forename: Marc
authors.initials: M
authors.lastname: De Maeyer
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018929:Cell Culture Techniques; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology*; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D007113:Immunity, Innate; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014584:User-Computer Interface; D016662:Virus Integration / Q000187:drug effects / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C548807:LEDGF peptide (361-370), human; D010446:Peptide Fragments; D044005:Tetrahydroisoquinolines; D019427:HIV Integrase
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