Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions

作者：Sanchez Tino Wilson; Debnath Bikash; Christ Frauke; Otake Hiroyuki; Debyser Zeger; Neamati Nouri^*

来源：Bioorganic & Medicinal Chemistry, 2013, 21(4): 957-963.

DOI：10.1016/j.bmc.2012.12.012

• HIV
• Integrase
• LEDGF/p75
• Antiviral
• N-Acylhydrazones
• Hydrazines

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 IC50 value of 400 nM. 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.

• 出版日期2013-2-15