Structural and functional study of efflux pumps involved in drug resistance

• Main Author: Martinez Jaramillo, Lorena Marcela
• Language: English
• Published: Université Claude Bernard - Lyon I 2014
• Subjects: [SDV:SA] Life Sciences/Agricultural sciences; [SDV:SA] Sciences du Vivant/Sciences agricoles; ABC transporters; P-glycoprotein; Screening; X-ray structures; Binding sites
• Online Access: http://tel.archives-ouvertes.fr/tel-00985593; http://tel.archives-ouvertes.fr/docs/00/98/55/93/PDF/TH2014_Martinez-Jaramillo_Lorena-Marcela.pdf

Resistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane which prevents the accumulation of anticancer, antiviral, antifungal and antibacterial drugs in target cells. Three human ABC transporters are particularly involved in MDR phenotype: P-gp/ABCB1, MRP1/ABCC1 and BCRP/ABCG2. Among the different approaches used to overcome the resistance linked to these transporters, the development of non-substrate drugs MDR-ABC transporters has been described. Here, new class of HIV-1 protease inhibitors not recognized by P-gp/BCRP were identified, promising to be attractive candidates to HAART therapy. Since the determination of the X-ray structures in different conformations is a key point to understand how MDR-ABC transporters translocate drugs across the plasma membrane, the crystal structures of three inward-facing conformations of mouse P-gp were resolved. One structure has a camel nanobody bound to the C-terminal side of the first nucleotide-binding domain, revealing a unique epitope on P-gp and freezing a new open-inward conformation. Finally, the enzymatic characterization of two inhibitors co-crystallized with the mouse P-gp has allowed to localize two main binding sites by which drugs efflux occurs. These results bring new findings of the drug-efflux mechanism and offer the possibility to target more precisely those sites to develop modulators of this pump