The amphipathic
peptide duramycin is in clinical development for the treatment of
cystic fibrosis. It is deposited in cellular membranes where it binds to
phosphatidylethanolamine.
Duramycin may thereby change the biophysical membrane properties and perturb the function of
ion channels. If so, in heart tissue, its application carries the risk to elicit
cardiac arrhythmias. In fact, premature ventricular complexes were observed in the electrocardiogram during toxicological testing in dogs. To study the arrhythmogenic potential of
duramycin, we investigated its effects on currents through voltage-gated hERG
potassium,
sodium, and
calcium channels in native cells, and using a heterologous expression system, by means of the whole-cell patch clamp technique;
duramycin bath concentrations between 1 nM and 0.1 microM did not generate any effects on these currents. Concentrations >or=0.3 microM, however, reduced the amplitudes of all investigated currents. Moreover,
sodium current fast inactivation kinetics was slowed in the presence of
duramycin. A further rise in
duramycin bath concentration (>or=3.3 microM) induced a leak current consistent with pore formation. The reported effects of
duramycin on
ion channel function are likely to arise from a change in the biophysical properties of the membrane rather than from a specific interaction of the
peptide with
ion channel proteins. Under therapeutic conditions (i.e., administration via inhalation),
duramycin plasma concentrations are below 0.5 nM. Thus, upon inhalation,
duramycin has a large safety margin and is highly unlikely to elicit arrhythmias.