The Regents Of The University Of California and Bachem Bioscience Inc. | Date: 2015-05-28
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.
Chauhan S.S.,Bachem Bioscience Inc. |
Wilk H.J.,Bachem Bioscience Inc.
Tetrahedron Letters | Year: 2010
Stereocontrolled synthesis of (S)-Fmoc-β-nitroalanine (20) was accomplished from (R)-Fmoc-Ser(tBu)-OH (14) in a total of six steps via an oxime. The oxime (17) was obtained from (R)-Fmoc-Ser(tBu)-H (16), which in turn was obtained by reduction of Weinreb amide (15). Oxidation of oxime was realized with peroxytrifluoroacetic acid at a neutral pH at 0 °C. After removal of the tBu protecting group with 90% TFA/H2O, the hydroxyl group was oxidized with Jones reagent to afford (S)-Fmoc-β-nitroalanine (20) in overall good yield. © 2010 Elsevier Ltd. All rights reserved.
Rangaraju S.,University of California at Irvine |
Khoo K.K.,Walter and Eliza Hall Institute of Medical Research |
Khoo K.K.,University of Melbourne |
Feng Z.-P.,University of Melbourne |
And 9 more authors.
Journal of Biological Chemistry | Year: 2010
Peptide toxins found in a wide array of venoms block K+ channels, causing profound physiological and pathological effects. Here we describe the first functional K+ channel-blocking toxin domain in a mammalian protein. MMP23 (matrix metalloprotease 23) contains a domain (MMP23TxD) that is evolutionarily related to peptide toxins from sea anemones. MMP23TxD shows close structural similarity to the sea anemone toxins BgK and ShK. Moreover, this domain blocks K+ channels in the nanomolar to low micromolar range (Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4, in decreasing order of potency) while sparing other K+ channels (Kv1.2, Kv1.5, Kv1.7, and KCa3.1). Full-length MMP23 suppresses K + channels by co-localizing with and trapping MMP23 TxD-sensitive channels in the ER. Our results provide clues to the structure and function of the vast family of proteins that contain domains related to sea anemone toxins. Evolutionary pressure to maintain a channel-modulatory function may contribute to the conservation of this domain throughout the plant and animal kingdoms. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.