4z7p
X-ray structure of racemic ShK Q16K toxinX-ray structure of racemic ShK Q16K toxin
Structural highlights
FunctionK1A_STIHL Inhibits voltage-dependent potassium channels. Inhibits Kv1.3/KCNA3 potently and also blocks Kv1.1/KCNA1, Kv1.4/KCNA4, and Kv1.6/KCNA6 at subnanomolar concentrations.[1] Publication Abstract from PubMedTo realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15x selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000x over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys. Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.,Murray JK, Qian YX, Liu B, Elliott R, Aral J, Park C, Zhang X, Stenkilsson M, Salyers K, Rose M, Li H, Yu S, Andrews KL, Colombero A, Werner J, Gaida K, Sickmier EA, Miu P, Itano A, McGivern J, Gegg CV, Sullivan JK, Miranda LP J Med Chem. 2015 Aug 31. PMID:26288216[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||