Channel forming peptides

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues

Reexamination Certificate

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C530S350000

Reexamination Certificate

active

07829661

ABSTRACT:
The present invention provides a family of peptides based upon the M2GlyR sequence. These peptides are derivatives of the M2GlyR sequence and can be modified at their ends to include a plurality of polar amino acid residues to enhance their solubility. Particularly preferred derivatives include portions of the M2GlyR sequence which are palindromic to another portion of the peptide or to the M2GlyR sequence itself. Preferably these portions are at least 7 amino acid residues in length. Peptides embraced by the present invention are characterized by having greater effects on the transepithelial electrical resistance of cells at lower concentrations. Peptides of the present invention have been shown to increase Isc in MDCK epithelial cell monolayers with half maximal effects observed at or below 30 μM, a nearly 10-fold improvement over any peptide previously characterized in the M2GlyR family. Additionally, peptides of the invention have been shown to increase transepithelial electrical conductance and modulate the permeability of tight junctions in epithelial cells.

REFERENCES:
patent: 5368712 (1994-11-01), Tomich et al.
patent: 5922840 (1999-07-01), Tomich et al.
patent: 6077826 (2000-06-01), Tomich et al.
patent: WO9726905 (1997-07-01), None
Broughman, J.R., K. Mitchell, T. Iwamoto, B.D. Schultz, and J.M. Tomich. Amino-terminal Modification of a Channel-forming Peptide Increases Capacity for Epithelial Anion Secretion.Am. J. Physiol:(Cell Physiol.) 280; C451-C458, 2001.
Esposito, G., B. Dhanapal, P. Dumy, V. Varma, M. Mutter, and G. Bodenhausen. Lysine as Helix C-capping Residue in a Synthetic Peptide.Biopolymers41, 27-35 (1997).
Gao, L., J.R. Broughman, T. Iwamoto, J.M. Tomich, C.J> Venglarik, J.J. Forman. Synthetic Chloride Channel Restores Glutathione Secretion in Cystic Fibrosis Airway Epithelia.Am. J. Physiol. Lung Cell Mol. Physiol. 281:L24-L30, 2001.
Mitchell, K.E., J.M. Tomich, T. Iwamoto, and L.C. Freeman. A Synthetic Peptide Based on a Glycine-gated Chloride Channel Induces a Novel Chloride Conductance in Isolated Epithelial Cells.Biochim. Biophys. Acta1466, 47-60 (2000).
Reddy, L.G., T. Iwamoto, J.M. Tomich, and M. Montal. Synthetic Peptides and Four-helix Bundle Proteins as Model Systems for the Pore-forming Structure of Channel Proteins. II. Transmembrane Segment M2 of the Brain Glycine Receptor Channel Is a Plausible Candidate for the Pore-lining Structure.J. Biol. Chem. 268, 14608-14615 (1993).
Tomich, J.M., D.P. Wallace, K. Henderson, R. Brandt, C.A. Ambler, A.J. Scott, K.E. Mitchell, G. Radke, J.J. Grantham, L.P. Sullivan, and T. Iwamoto. Aqueous Solubilization of Transmembrane Peptide Sequences with Retention of Membrane Insertion and Function.Biophys J. 74, 256-267 (1998).
Tomich, J.M. Amphipathic Helices in Channel-Forming Structures.The Amphipathic HelixChap. 9, pp. 221-254 (1993).
Wallace, D.P., J.M. Tomich, T. Iwamoto, K. Henderson, J.J. Grantham, and L.P. Sullivan. A Synthetic Peptide Derived from the Glycine-gated CI-channel Generates CI- channel induces transepithelial CI- and fluid secretion by Epithelial Monolayers.Am. J. Physiol: 272 (Cell Physiol. 41) C1672-C1679 (1997).
Wallace, D.P., J.M. Tomich, J. Eppler, T. Iwamoto, J.J. Grantham, and L.P. Sullivan. A Synthetic Channel-Forming Peptide Induces CI- Secretion: Modulation by Ca2+-dependent K+Channels.Biochim. Biophys. Acta1464, 69-82 (2000).

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