Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels

Jae H. Park, Kevin P. Carlin, Gang Wu, Victor I. Ilyin, Laszlo L. Musza, Paul R. Blake, Donald J. Kyle

Research output: Contribution to journalArticlepeer-review

Abstract

The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.7 and Nav1.2 channels were investigated. Other tail region modifications to this chimera explored the effects of tail length and tertiary structure on sodium channel activity. In addition, the activity of various C-terminal modifications of the native ProTx II was assayed and resulted in the identification of protoxin II-NHCH3, a molecule with greater potency against Nav1.7 channels (IC50 = 42 pM) than the original ProTx II.

Original languageEnglish (US)
Pages (from-to)6623-6631
Number of pages9
JournalJournal of medicinal chemistry
Volume57
Issue number15
DOIs
StatePublished - Aug 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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