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Screening for Antiviral Inhibitors of the HIV Integrase–LEDGF/p75 Interaction Using the AlphaScreen™ Luminescent Proximity Assay

2008; Elsevier BV; Volume: 13; Issue: 5 Linguagem: Inglês

10.1177/1087057108317060

2472-5560

Yan Hou, Debra E McGuinness, Andrew Prongay, Boris Feld, Paul Ingravallo, Robert A. Ogert, Charles A. Lunn, John A. Howe,

Biochemical and Molecular Research

Small-molecule inhibitors of HIV integrase (HIV IN) have emerged as a promising new class of antivirals for the treatment of HIV/AIDS. The compounds currently approved or in clinical development specifically target HIV DNA integration and were identified using strand-transfer assays targeting the HIV IN/viral DNA complex. The authors have developed a second biochemical assay for identification of HIV integrase inhibitors, targeting the interaction between HIV IN and the cellular cofactor LEDGF/p75. They developed a luminescent proximity assay (AlphaScreen) designed to measure the association of the 80-amino-acid integrase binding domain of LEDGF/p75 with the 163-amino-acid catalytic core domain of HIV IN. This assay proved to be quite robust (with a Z' factor of 0.84 in screening libraries arrayed as orthogonal mixtures) and successfully identified several compounds specific for this protein-protein interaction.