Partial characterization of predicted ABCC5 inhibitors by the aid of human erythrocyte inside-out vesicles

Abstract

ABCC5 is a member of the superfamily of ABC-transporters, and it has been identified as an efflux transporter of cGMP. This transporter is also involved in export of antibiotic and cytostatic drugs from target cells, and as such represents a challenge in treatment of cancer and infectious diseases. In order to find inhibitors to ABCC5 mediated drug efflux, compounds predicted as potent inhibitors by virtual ligand screening (VLS) were chosen for in-vitro studies by the use of human erythrocyte inside-out vesicles (IOV). The procedure for IOV preparation was improved, and transport assays were performed where the inhibiting effects of the various compounds on transport of cGMP into inside-out vesicles were measured. Several of these compounds showed a potent inhibiting effect on cGMP transport, and the few that were chosen for further characterization showed more potent inhibition of ABCC5 than the known ABCC5 and PDE5 inhibitor sildenafil.