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Reversing the direction of drug transport mediated by the human multidrug transporter P-glycoprotein

2020; National Academy of Sciences; Volume: 117; Issue: 47 Linguagem: Inglês

10.1073/pnas.2016270117

1091-6490

Andaleeb Sajid, Sabrina Lusvarghi, Megumi Murakami, Eduardo E. Chufán, Biebele Abel, Michael M. Gottesman, Stewart R. Durell, Suresh V. Ambudkar,

DNA and Nucleic Acid Chemistry

Significance The multidrug transporter P-glycoprotein protects tissues from xenobiotics and other toxic compounds by pumping them out of cells. This transporter has been implicated in altering the bioavailability of chemotherapeutic drugs and in the development of multidrug resistance in tumor cells. Despite decades of research, the modulation of P-glycoprotein to overcome drug resistance in the clinic has not been successful. Here, by substituting a group of 14 conserved residues in homologous transmembrane helices 6 and 12 with alanine, we generated a mutant that exhibits a change in the direction of transport from export to import for certain drug substrates including the taxol derivative flutax-1. The ability to convert P-glycoprotein into a drug importer provides a strategy to combat cancer drug resistance.