J Med Chem. 2015 Aug 19. [Epub ahead of print]
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 JG, Gegg CV, Sullivan JK, Miranda LP.
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 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.