Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels

Biochemical Pharmacology
S ZhuJ Tytgat

Abstract

The design of animal toxins with high target selectivity has long been a goal in protein engineering. Based on evolutionary relationship between the Drosophila antifungal defensin (drosomycin) and scorpion depressant Na(+) channel toxins, we exploited a strategy to create a novel chimeric molecule (named drosotoxin) with high selectivity for channel subtypes, which was achieved by using drosomycin to substitute the structural core of BmKITc, a depressant toxin acting on both insect and mammalian Na(+) channels. Recombinant drosotoxin selectively inhibited tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion (DRG) neurons with a 50% inhibitory concentration (IC(50)) of 2.6+/-0.5muM. This chimeric peptide showed no activity on K(+), Ca(2+) and TTX-sensitive (TTX-S) Na(+) channels in rat DRG neurons and Drosophila para/tipE channels at micromolar concentrations. Drosotoxin represents the first chimeric toxin and example of a non-toxic core scaffold with high selectivity on mammalian TTX-R Na(+) channels.

References

Jul 8, 1999·Proceedings of the National Academy of Sciences of the United States of America·M S Gold
Sep 22, 1999·European Journal of Biochemistry·L D PossaniJ Tytgat
Apr 18, 2002·The Journal of Biological Chemistry·Naoki FujitaniKeiichi Kawano
Dec 11, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·C-G WangM Pelhate
Oct 4, 2003·Nature Reviews. Drug Discovery·Richard J Lewis, Maria L Garcia
Oct 27, 2004·Toxicon : Official Journal of the International Society on Toxinology·Allan M Torres, Philip W Kuchel
Nov 19, 2004·The Journal of Biological Chemistry·Yucheng XiaoSongping Liang
Mar 1, 2005·Toxicon : Official Journal of the International Society on Toxinology·Frank BosmansJan Tytgat
Sep 7, 2005·Cellular and Molecular Life Sciences : CMLS·S ZhuJ Tytgat
Nov 9, 2005·Toxicon : Official Journal of the International Society on Toxinology·Ricardo C Rodríguez de la Vega, Lourival D Possani
Nov 2, 2006·Proceedings of the National Academy of Sciences of the United States of America·J EkbergR J Lewis
Dec 16, 2006·Current Medicinal Chemistry·Ron C Hogg
Dec 16, 2006·Protein Expression and Purification·Yuzhe YuanShunyi Zhu
Jan 2, 2007·Toxicon : Official Journal of the International Society on Toxinology·Michael GurevitzDalia Gordon
Jan 12, 2007·Toxicon : Official Journal of the International Society on Toxinology·Dalia GordonMichael Gurevitz
Jan 24, 2007·Toxicon : Official Journal of the International Society on Toxinology·William A CatterallTodd Scheuer
Apr 3, 2007·Pharmacology & Therapeutics·Márcia Renata MortariWagner Ferreira dos Santos
Oct 24, 2007·The International Journal of Biochemistry & Cell Biology·J EkbergD J Adams
Nov 13, 2007·Nature Biotechnology·Chengshu Wang, Raymond J St Leger
Jan 8, 2008·Toxicon : Official Journal of the International Society on Toxinology·Caihuan TianShunyi Zhu
Feb 22, 2008·Molecular Immunology·Shunyi ZhuRichard L Gallo
Sep 11, 2008·Current Pharmaceutical Design·Raymond S Norton, Stefan I McDonough
Sep 11, 2008·Current Pharmaceutical Design·Bert BillenJan Tytgat
Sep 11, 2008·Current Pharmaceutical Design·Stéphanie MouhatJean-Marc Sabatier
Jun 6, 2009·Expert Review of Proteomics·Pierre Escoubas, Glenn F King
Jul 31, 2009·Annual Review of Genomics and Human Genetics·Bryan G FryRicardo C Rodríguez de la Vega
Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Nannette Y YountMichael R Yeaman
Nov 3, 2009·Current Biology : CB·Yael T AminetzachHopi E Hoekstra
Mar 12, 2010·Toxicon : Official Journal of the International Society on Toxinology·Yuzhe YuanShunyi Zhu

❮ Previous
Next ❯

Citations

May 19, 2011·The Journal of Pharmacology and Experimental Therapeutics·Michael J WilsonDoju Yoshikami
Jan 16, 2014·Molecular Biology and Evolution·Shunyi ZhuJan Tytgat
Jul 19, 2011·Biochemical and Biophysical Research Communications·Bin GaoShunyi Zhu
Jan 31, 2012·Gene·Emily S W Wong, Katherine Belov
Dec 31, 2016·Toxins·Xueli WangShunyi Zhu
Aug 11, 2017·The FEBS Journal·Chan-Hee KimNam Gyu Park
Mar 13, 2012·Pharmacological Reviews·Richard J LewisMacDonald J Christie

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.