Synthesis of the cardiac inotropic polypeptide anthopleurin‐A

MICHAEL W. PENNINGTON, INNA ZADENBERG, MICHAEL E. BYRNES, RAYMOND S. NORTON, WILLIAM R. KEM

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Abstract

The sea anemone polypeptide anthopleurin‐A (AP‐A) at nanomolar concentrations enhances myocardial contractility without affecting automaticity. It has a therapeutic index higher than that of the digitalis glyco‐sides, and may serve as a molecular model for designing a new class of inotropic drugs acting on the myocardial Na channel at site 3. AP‐A is a 49 residue peptide crosslinked by three disulfide bonds; its tertiary structure has been determined by NMR. Here we report the solid‐phase synthesis of this polypeptide. Synthetic AP‐A displayed CD and NMR spectra identical with those of the natural toxin; it possessed 94±15% of the inotropic activity of natural AP‐A. Therefore, it is feasible to prepare various type 1 sea anemone toxin analogs by solid‐phase chemical synthesis in order to identify side chains important for peptide folding and interaction with sodium channels.

Original languageEnglish
Pages (from-to)463-470
Number of pages8
JournalInternational Journal of Peptide and Protein Research
Volume43
Issue number5
DOIs
Publication statusPublished - 1994
Externally publishedYes

Keywords

  • anthopleurin‐A
  • heart inotropic agent
  • sea anemone toxin
  • sodium channel
  • solid‐phase synthesis

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