Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes.

Molecular Pharmacology
M W PenningtonK G Chandy

Abstract

Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a sin...Continue Reading

References

May 1, 1995·Toxicon : Official Journal of the International Society on Toxinology·O CastañedaE Karlsson
Apr 1, 1996·Nature Structural Biology·J E TudorR S Norton
Feb 1, 1996·Journal of Molecular Graphics·R KoradiK Wüthrich
Dec 1, 1996·Journal of Biomolecular NMR·R A LaskowskiJ M Thornton
Jun 17, 1998·The Journal of General Physiology·W ZhouT E DeCoursey
Nov 26, 1998·The Journal of Biological Chemistry·K KalmanK G Chandy
Jan 6, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·C BeetonE Béraud
Mar 10, 2001·Nature·P ChampagneG Pantaleo
Jun 1, 2001·Toxicon : Official Journal of the International Society on Toxinology·K G ChandyG A Gutman
Jul 28, 2001·The New England Journal of Medicine·C N EllisUNKNOWN Alefacept Clinical Study Group
Oct 17, 2001·The Journal of Clinical Investigation·S Markovic-PleseR Martin
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·C BeetonE Béraud
Apr 3, 2002·The Journal of Clinical Investigation·Vissia VigliettaDavid A Hafler
Jun 5, 2003·The Journal of Clinical Investigation·Heike WulffK George Chandy
Jun 5, 2003·Proteins·Rong ChenZhiping Weng
Oct 28, 2003·Proceedings of the National Academy of Sciences of the United States of America·Stefan O SchönlandCornelia M Weyand
Oct 28, 2003·Proteins·Li LiZhiping Weng
Dec 31, 2003·Methods in Enzymology·András Fiser, Andrej Sali
Feb 7, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Feng Yun YueMario A Ostrowski
May 4, 2004·Annals of Neurology·Pia KivisäkkRichard M Ransohoff
Jun 28, 2005·Proceedings of the National Academy of Sciences of the United States of America·Christopher A KlebanoffNicholas P Restifo
Jul 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Horea RusPeter A Calabresi
Nov 23, 2005·The Journal of Experimental Medicine·Godelieve J de BreeRené A W van Lier
Nov 3, 2006·Expert Review of Neurotherapeutics·Mark S Wallace
Nov 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·Christine BeetonK George Chandy
Feb 3, 2007·The Journal of Investigative Dermatology·Philippe AzamHeike Wulff
Nov 7, 2007·Nucleic Acids Research·Eldon L UlrichJohn L Markley
Nov 7, 2007·The Journal of Biological Chemistry·Christine BeetonRaymond S Norton
Jul 1, 1995·Journal of Biomolecular NMR·C BartelsK Wüthrich

❮ Previous
Next ❯

Citations

Dec 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Zoltan TakacsSteve A N Goldstein
May 29, 2012·The Journal of Pharmacology and Experimental Therapeutics·Eric J TarchaShawn P Iadonato
May 24, 2013·PloS One·Romain FélixFlorence Velge-Roussel
Mar 24, 2011·Future Medicinal Chemistry·Russell W Teichert, Baldomero M Olivera
Dec 7, 2013·Neuro-oncology·Ying PengYamei Tang
Jun 1, 2014·Toxicon : Official Journal of the International Society on Toxinology·Adam BartokZoltan Varga
Nov 19, 2014·Future Medicinal Chemistry·Serdar Kuyucak, Raymond S Norton
Mar 2, 2010·The Journal of Biological Chemistry·Sébastien Dutertre, Richard J Lewis
Oct 11, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Maria I LioudynoMichael T Alkire
Dec 5, 2015·Expert Opinion on Therapeutic Targets·Mireia Pérez-VerdaguerAntonio Felipe
Sep 24, 2011·Expert Opinion on Biological Therapy·Glenn F King
Dec 9, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Liang JinJoseph A Nicolazzo
Dec 2, 2014·Pharmacology & Therapeutics·Katja SchmitzIrmgard Tegeder
Aug 27, 2011·Toxicon : Official Journal of the International Society on Toxinology·Victor ChiK George Chandy
Feb 16, 2016·Biochemistry. Biokhimii︠a︡·A I KuzmenkovA A Vassilevski
Mar 14, 2009·Toxicon : Official Journal of the International Society on Toxinology·Dusan Suput
Mar 17, 2009·Toxicon : Official Journal of the International Society on Toxinology·Raymond S Norton
Nov 10, 2015·The Journal of Physical Chemistry. B·Eva MeirovitchJordan H Chill
Jan 14, 2012·Drug Development Research·Jenny Lam, Heike Wulff
Jun 5, 2012·Toxicon : Official Journal of the International Society on Toxinology·Shih Chieh ChangRaymond S Norton
Oct 24, 2014·The AAPS Journal·Jennifer L FurmanMichael J Hunter
Apr 9, 2017·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Mark R TannerChristine Beeton
Apr 12, 2017·Expert Opinion on Drug Discovery·Raymond S Norton
Jun 23, 2009·Expert Opinion on Therapeutic Targets·Srikant RangarajuK George Chandy
Jan 21, 2015·Marine Drugs·Michael W PenningtonChristine Beeton
Jan 11, 2018·Toxins·Peter J PrentisRaymond S Norton
May 9, 2014·Bioinformatics and Biology Insights·Angélica Sabogal-ArangoJanneth González
Apr 30, 2010·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Raymond S Norton
Mar 20, 2014·The Journal of Biological Chemistry·Shyny KoshyChristine Beeton
Jun 4, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sandeep ChhabraK George Chandy
Feb 2, 2018·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Susumi Hatakeyama

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