MULTIDRUG-RESISTANCE DRUG-BINDING PEPTIDES GENERATED BY USING A PHAGEDISPLAY LIBRARY

A phage display library of random decapeptides was used to generate pe ptide ligands that can bind multidrug-resistance (MDR) drugs mimicking , in this respect, the drug-binding activity of P-glycoprotein. Seven peptide sequences were identified that specifically bound doxorubicin, Five of these sequences expressed the core consensus motif WXXW, The displacement assay showed that the phages expressing these peptides bo und MDR type drugs (vinblastine, doxorubicin, verapamil, and genistein ) with the same selectivity as P-glycoprotein and did not interact wit h non-MDR type drugs, such as arabinosylcytosine (Ara-C) and melphalan . One of the selected peptides that showed a highest capacity for the binding (VCDWWGWGIC) was synthesized and displayed competition with th e phage for doxorubicin binding. The structure modeling suggested that all the selected sequences contained a hydrophobic envelope in which MDR drugs could be docked with substantial energy minimization. Wester n blot analysis showed that monospecific antibody obtained against the phage expressing VCDWWGWGIC peptide could specifically recognize P-gl ycoprotein in the membrane fraction of MDR phenotype MCF-7ADR cells. T he MDR drug-binding sequences generated during this work could provide an important tool for design and screening of new chemotherapeutic ag ents.