Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3

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• 作者：Justin K. Murray ; Yi-Xin Qian ; Benxian Liu ; Robin Elliott ; Jennifer Aral ; Cynthia Park ; Xuxia Zhang ; Michael Stenkilsson ; Kevin Salyers ; Mark Rose ; Hongyan Li ; Steven Yu ; Kristin L. Andrews ; Anne Colombero ; Jonathan Werner ; Kevin Gaida ; E. Allen Sickmier ; Peter Miu ; Andrea Itano ; Joseph McGivern ; Colin V. Gegg ; John K. Sullivan ; Les P. Miranda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6784-6802
• 全文大小：840K
• ISSN：1520-4804

文摘

To 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鈥揳ctivity 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 15脳 selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000脳 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.