Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3.
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.
Justin K
JK
Murray
Yi-Xin
YX
Qian
Benxian
B
Liu
Robin
R
Elliott
Jennifer
J
Aral
Cynthia
C
Park
Xuxia
X
Zhang
Michael
M
Stenkilsson
Kevin
K
Salyers
Mark
M
Rose
Hongyan
H
Li
Steven
S
Yu
Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
Kristin L
KL
Andrews
Anne
A
Colombero
Jonathan
J
Werner
Kevin
K
Gaida
E Allen
EA
Sickmier
Peter
P
Miu
Andrea
A
Itano
Joseph
J
McGivern
Colin V
CV
Gegg
John K
JK
Sullivan
Les P
LP
Miranda
D000818:Animals; D016466:CHO Cells; D003064:Cnidarian Venoms / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000378:metabolism; D007376:Interleukin-2 / Q000097:blood / Q000378:metabolism; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D003064:Cnidarian Venoms; D020381:Interleukin-17; D007376:Interleukin-2; D051664:Kv1.3 Potassium Channel; D010455:Peptides; C095391:ShK neurotoxin; D051662:Kv1.1 Potassium Channel; D011092:Polyethylene Glycols; D007371:Interferon-gamma