FERROCENOYL DERIVATIVES OF ALAMETHICIN - REDOX-SENSITIVE ION CHANNELS

The synthesis and single-channel characterization of two redox-active C-terminal derivatives of alamethicin are herein described. The reduce d [Fe(II)] forms of ferrocenoyl-alamethicin (Fc-ALM) and 1'-carboxyfer rocenoyl-alamethicin (cFc-ALM) are shown to form voltage-dependent ion channels at cis positive potentials in planar lipid bilayers (PLB) wi th conductance properties similar to those of alamethicin. In situ oxi dation of Fc-ALM [to Fe(III)] in the PLB apparatus causes a time-depen dent elimination of channel openings, which can be restored by an incr ease in the transbilayer potential. In contrast, oxidation of cFc-ALM leads to the formation of shorter-lived channels. Pretreatment of the ferrocenoyl peptides with oxidizing agent alters their single-channel properties in a qualitatively similar manner, establishing that the ch anges in channel properties in the presence of oxidizing agents are du e specifically to ferrocenoyl oxidation. We suggest that the redox sen sitivity of these ferrocene-containing ion channels may be governed by a combination of the following factors: (1) changes in hydrophobicity ; (2) alteration of peptide molecular dipole; and (3) alterations in t endencies toward self-association. However, oxidation induced changes in peptide conformation cannot be ruled out. Our results provide evide nce that it is possible to engineer channel-forming peptides that resp ond to specific changes in the chemical environment.