Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3
| Autor: | Kevin Gaida, Xuxia Zhang, Robin Elliott, Benxian Liu, Andrea Itano, Cynthia Park, Justin K. Murray, Colin V. Gegg, Jennifer Aral, Les P. Miranda, Joseph G. McGivern, Hongyan Li, Anne Colombero, E. Allen Sickmier, Kevin Salyers, Michael Stenkilsson, Jonathan Werner, Steven Yu, Mark J. Rose, John K. Sullivan, Yi-Xin Qian, Peter Miu, Kristin L. Andrews |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Patch-Clamp Techniques T-Lymphocytes Peptide CHO Cells Pharmacology Crystallography X-Ray Polyethylene Glycols Rats Sprague-Dawley Interferon-gamma Mice Structure-Activity Relationship Cnidarian Venoms Cricetulus Dogs Species Specificity Drug Discovery Animals Humans Structure–activity relationship Patch clamp Ion channel Kv1.1 Potassium Channel chemistry.chemical_classification Kv1.3 Potassium Channel Stichodactyla helianthus biology Chemistry Interleukin-17 Stereoisomerism biology.organism_classification Potassium channel Molecular Docking Simulation Macaca fascicularis Electrophysiology HEK293 Cells Biochemistry Interleukin-2 Molecular Medicine Peptides |
| Zdroj: | Journal of Medicinal Chemistry. 58:6784-6802 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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-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 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (1000× 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. |
| Databáze: | OpenAIRE |
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