Synthesis of the cardiac inotropic polypeptide anthopleurin‐A

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

doi:10.1111/j.1399-3011.1994.tb00545.x

Synthesis of the cardiac inotropic polypeptide anthopleurin‐A

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

Research output: Contribution to journal › Article › Research › peer-review

6 Citations (Scopus)

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 language	English
Pages (from-to)	463-470
Number of pages	8
Journal	International Journal of Peptide and Protein Research
Volume	43
Issue number	5
DOIs	https://doi.org/10.1111/j.1399-3011.1994.tb00545.x
Publication status	Published - 1994
Externally published	Yes

Keywords

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

Access to Document

10.1111/j.1399-3011.1994.tb00545.x

Link to publication in Scopus

Cite this

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title = "Synthesis of the cardiac inotropic polypeptide anthopleurin‐A",

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.",

keywords = "anthopleurin‐A, heart inotropic agent, sea anemone toxin, sodium channel, solid‐phase synthesis",

author = "PENNINGTON, {MICHAEL W.} and INNA ZADENBERG and BYRNES, {MICHAEL E.} and NORTON, {RAYMOND S.} and KEM, {WILLIAM R.}",

year = "1994",

doi = "10.1111/j.1399-3011.1994.tb00545.x",

language = "English",

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T1 - Synthesis of the cardiac inotropic polypeptide anthopleurin‐A

AU - PENNINGTON, MICHAEL W.

AU - ZADENBERG, INNA

AU - BYRNES, MICHAEL E.

AU - NORTON, RAYMOND S.

AU - KEM, WILLIAM R.

PY - 1994

Y1 - 1994

N2 - 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.

AB - 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.

KW - anthopleurin‐A

KW - heart inotropic agent

KW - sea anemone toxin

KW - sodium channel

KW - solid‐phase synthesis

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