title: The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy.
abstract: To accomplish their viral life cycle, lentiviruses such as HIV highjack host proteins, the so-called cellular co-factors of replication. Lens Epithelium-derived Growth factor (LEDGF/p75), a transcriptional co-activator, is a co-factor of HIV-integrase (IN) and is required for the tethering and correct integration of the viral genome into the host chromatin. Due to its important role in HIV-replication the LEDGF/p75-IN interaction is an attractive antiviral novel target for the treatment of HIV/AIDS. Intensive drug discovery efforts over the past years have validated the LEDGF/p75-IN interaction as a drugable target for antiviral therapy and have resulted in the design and synthesis of LEDGINs, small molecule inhibitors binding to the dimer interface of HIV-integrase and inhibiting viral replication with a dual mechanism of action: potent inhibition of the LEDGF/p75-IN protein-protein interaction and allosteric inhibition of the catalytic function. Furthermore they inhibit both early and late steps of the replication cycle which increases their potential for further clinical development. In this review we will highlight the research validating the LEDGF/p75-IN interaction as a target for anti-HIV drug discovery and the recent advances in the design and development of LEDGINs.
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Division of Molecular Medicine, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. frauke.christ@med.kuleuven.be
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000494:pharmacology*; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000085:Acetates; D019428:HIV Integrase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase