Kvl.3 Selective Peptides Based upon iV-Terminal Extension and Internal Substitutions of ShK Toxin

摘要

With more than 80 different types of autoimmune disorders affecting all organ systems in the human body, finding a drug which would treat patients at the root cause of these diseases has been a quest of our mutual labs for the past two decades. These diseases may range from mild skin disorders such as psoriasis, widely distributed joint damage such as in rheumatoid arthritis, destruction of specific cells such as P cells in type-1 diabetes to more complex disorders affecting central nervous system such as multiple sclerosis. Current treatments involve the use of broad immunosuppressants, which may open the door to opportunistic infections. Through work pioneered with the Chandy lab, we have shown that the channel phenotypes of these autoantigen specific T-eells have preferentially upregulated the K_v1.3 channel to balance Ca~(+2) influx upon activation. A sea anemone derived peptide named ShK is one of the most potent Kvl .3 blockers described (IC50 =10 pM), however it lacks specificity and blocks K_vl.l and Kv1.5 also at pM levels [1,2]. Through many years of engineering, we have progressed one of our peptides, Dalazatide (formerly ShK-186) to the clinic for its selective block of K_v1.3 channels as a means of treating autoimmune diseases. In our current work, we have built upon our findings to continue to improve the selectivity of ShK-derived analogs and have recently reported selectivity profiles of more than lOOOx for K_v1.3 versus K_vl.l. We have improved the drugability of ShK [3,4].