title: Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions.
abstract: Human lens epithelium-derived growth factor (LEDGF)/p75 plays an important role in the HIV life cycle by stimulating integrase (IN)-led viral DNA integration into cellular chromosomes. Mechanistic studies show the majority of IN inhibitors chelate magnesium ions in the catalytic active site, a region topologically distant from the LEDGF/p75 binding site. Compounds disrupting the formation of LEDGF/p75 and IN complexes serve as a novel mechanistic approach different from current antiretroviral therapies. We previously built pharmacophore models mimicking LEDGF/p75 residues and identified four classes of LEDGF/p75-IN inhibitors. Substructure and similarity searches yielded additional LEDGF/p75-IN inhibitors containing an acylhydrazone moiety. The most potent of the acylhydrazones inhibited LEDGF/p75-IN interaction with an IC(50) value of 400nM. We explored structure-activity relationships (SAR) and identified new acylhydrazones, hydrazines, and diazenes as lead molecules for further optimization. Two lead LEDGF/p75-IN inhibitors showed antiviral activity.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Tino Wilson
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otake
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D006835:Hydrazones / Q000737:chemistry; D007094:Imides / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry*; D062105:Molecular Docking Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D060066:Protein Interaction Maps / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D006834:Hydrazines; D006835:Hydrazones; D007094:Imides; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011994:Recombinant Proteins; C119380:lens epithelium-derived growth factor; C029424:hydrazine; D019427:HIV Integrase; C038867:diazene