Analogs of ShK toxin and their uses in selective inhibition of Kv1.3 potassium channels

摘要

Analogs of ShK toxin and methods for using such ShK analogs. The ShK analogs generally comprise ShK toxin attached to a chemical entity (e.g. an atom, molecule, group, residue, compound, moiety, etc.) that has an anionic charge. In some embodiments the chemical entity attached to the ShK toxin may comprise an amino acid residue. The ShK analogs may be administered to human or non-human animal subjects to cause inhibition of potassium channels or to otherwise treat diseases or disorders. In some embodiments, the chemical entity to which the ShK toxin is attached may be chosen to provide selective inhibition of certain potassium channels (e.g., Kv1.3 channels) over other potassium channels (e.g., Kv1.1 channels). In come embodiments, the chemical entity to which the ShK toxin is attached may include a fluorophore, thereby providing a fluorophore tagged ShK analog. Such fluorophore tagged ShK analogs may be used in flow cytometry alone, or in conjunction with class II tetramers that can detect autoreactive cells.

主权项

1. A method for causing inhibition of Kv1.3 potassium channels in a human or animal subject, said method comprising administering to the subject, in a form and amount that is effective to inhibit Kv1.3 potassium channels, a composition of matter comprising ShK toxin polypeptide attached to an organic chemical entity that has an anionic charge, wherein said chemical entity is covalently attached to the N-terminus of the ShK polypeptide through a 5-aminoethyloxyethyloxyacetic acid (AEEAc) linker, and wherein said chemical entity is selected from the group consisting of L-Tyr (PO3H2) and p-Phosphono-Phenylalanine (ppa).