HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

• Main Authors: Cara Andrea, Andreotti Mauro, Galluzzo Clementina, Verdoliva Antonio, Costi Roberta, Molinari Agnese, Dupuis Maria, Cianfriglia Maurizio, Di Santo Roberto, Palmisano Lucia
• Format: Article
• Language: English
• Published: BMC 2007-03-01
• Series: Retrovirology
• Online Access: http://www.retrovirology.com/content/4/1/17

<p>Abstract</p> <p>Background</p> <p>The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the <it>in vivo </it>efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their <it>in vitro </it>interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability.</p> <p>Results</p> <p>The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells.</p> <p>Conclusion</p> <p>To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.</p>