Synthesis of the cardiac inotropic polypeptide anthopleurin-A.
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 glycosides, 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.
Pennington
M W
MW
Bachem Bioscience Inc., Department of Peptide Chemistry, Philadelphia, Pennsylvania.
Zadenberg
I
I
Byrnes
M E
ME
Norton
R S
RS
Kem
W R
WR
D000595:Amino Acid Sequence; D000818:Animals; D016275:Atrial Function; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D002942:Circular Dichroism; D004586:Electrophoresis; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012615:Sea Anemones; D016339:Spectrometry, Mass, Fast Atom Bombardment
D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C012746:anthopleurin-A