Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators

Yuan Ping Pang, Thomas M. Kollmeyer, Feng Hong, Jong Cheol Lee, Pamela I. Hammond, Sharie P. Haugabouk, Stephen Brimijoin

Research output: Contribution to journalArticle

107 Scopus citations

Abstract

To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.

Original languageEnglish (US)
Pages (from-to)491-502
Number of pages12
JournalChemistry and Biology
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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