Ferrocenoyl Derivatives of Alamethicin:  Redox-Sensitive Ion Channels

• Published in: Biochemistry (Easton) Vol. 36; no. 5; pp. 1115 - 1122
• Main Authors: Schmitt, Jeffrey D, Sansom, M. S. P, Kerr, I. D, Lunt, G. G, Eisenthal, R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.02.1997
• Subjects: Alamethicin - analogs & derivatives; Alamethicin - chemical synthesis; Alamethicin - chemistry; Amino Acid Sequence; Electrochemistry; Ferrous Compounds; Indicators and Reagents; Ion Channels; Metallocenes; Models, Chemical; Molecular Sequence Data; Oxidation-Reduction; Structure-Activity Relationship
• DOI: 10.1021/bi962168w
• ISSN: 0006-2960

The synthesis and single-channel characterization of two redox-active C-terminal derivatives of alamethicin are herein described. The reduced [Fe(II)] forms of ferrocenoyl-alamethicin (Fc-ALM) and 1‘-carboxyferrocenoyl-alamethicin (cFc-ALM) are shown to form voltage-dependent ion channels at cis positive potentials in planar lipid bilayers (PLB) with conductance properties similar to those of alamethicin. In situ oxidation of Fc-ALM [to Fe(III)] in the PLB apparatus causes a time-dependent elimination of channel openings, which can be restored by an increase 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 changes in channel properties in the presence of oxidizing agents are due specifically to ferrocenoyl oxidation. We suggest that the redox sensitivity 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 tendencies toward self-association. However, oxidation induced changes in peptide conformation cannot be ruled out. Our results provide evidence that it is possible to engineer channel-forming peptides that respond to specific changes in the chemical environment.