Interaction of bioactive hydrophobic peptides with the human multidrug transporter

Abstract

In this report we demonstrate that various biologically active hydrophobic peptide derivatives, e.g., proteinase inhibitors, chemoattractants, ionophores, enkephalins, and immunosuppressants, stimulate a membrane ATPase activity associated with the human multidrug transporter (MDR1). The stimulation of the MDR1-ATPase by these agents does not correlate with their known biochemical or pharmacological activities but rather with their hydrophobicity. The peptides that show high-affinity interaction with the MDR1-ATPase also interfere strongly with fluorescent dye extrusion catalyzed by the multidrug transporter in intact cells and some have been shown to reverse drug resistance in cultured cells. These data suggest that several hydrophobic peptides behave as substrates of the multidrug transporter and may be used to modulate the chemotherapy resistance of tumor cells.

18FDG a PET tumor diagnostic tracer is not a substrate of the ABC transporter P-glycoprotein

“…Pgp is referred as a "hydrophobic vacuum cleaner", because it is believed to extract its substrates directly from the inner leaflet of the plasma membrane (Homolya et al, 1993;Ling, 1997, 1998). In accordance with it Pgp substrates are hydrophobic substances (Sarkadi et al, 1994) with logP values in the range of 2 to 5. For instance the logP value of verapamil is 3.78 (Buchwald and Bodor, 1998), and a competitive Pgp inhibitor cyclosporin A has a log P value of 2.92 (el Tayar et al, 1993).…”

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

“…Substantial biochemical evidence, including changes in drug binding, epitope accessibility, fluorescent and spectroscopic measurements, and protease susceptibility [53][54][55][56][57][58][59], suggests that TM segments undergo conformational change upon nucleotide binding. Pglycoprotein has high basal ATPase activity, and its ATPase activity can also be stimulated by drug binding [60][61][62][63]. in each cycle of ATP binding and hydrolysis, at least four conformations of P-glycoprotein (ligand-free, ATP-bound, ADP/Pi-bound after ATP hydrolysis, and ADP-bound) have been demonstrated [57].…”

The BH3 domain of BAD fused to the Antennapedia peptide induces apoptosis via its alpha helical structure and independent of Bcl-2

“…Previous studies of full length BAD 25,26 or the BH3 domain of BAD 6 ± 8 have not reported toxicity attributable to the alpha helical configuration. These studies demonstrated that over-expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by the full-length protein and peptide.…”