Constitution and conformation determine the biological activity of a peptide, as demonstrated by comparative investigations of the inhibition of cholate uptake in liver cells by somatostatin, antamanide, cyclolinopeptide A and 1 and 2. The crystal structure of 1 is the same as that of 2 over a wide range and both react strongly cytoprotectively.
Six cyclic retro‐analogues of the peptide hormone somatostatin have been synthesized using the solid phase technique. The peptides cyclo(‐Xaa1‐Phe2‐Thr3‐Lys4‐Ybb5‐Phe6‐) and cyclo(‐Phe1‐Xaa2‐Thr3‐Lys4‐Ybb5‐Phe6‐) with Xaa =d‐ or l‐Pro and Ybb =d‐ or l‐Trp were cyclized via the azide method. The conformations of the cyclic hexapeptides in DMSO‐d6 solution were determined by a number of homo‐ and heteronuclear two‐dimensional n.m.r.‐techniques including 2D rotating frame NOE‐spectroscopy. Two‐step coherence transfers, ROE and chemical exchange, are observed for the first time in ROESY spectra. The backbone conformation of the all‐trans cyclopeptides consists of a β‐turn containing the Pro residue in the position i + 1. These retro‐analogues of somatostatin exhibit a high activity in the inhibition of cholate and phalloidin uptake by liver cells (cytoprotective effect); however, the hormonal activities of the natural hormone are completely suppressed. The constitutional and conformational requirements for the cytoprotective activity are discussed.
Comparative investigations of the inhibition of cholate uptake in liver cells by the cyclopeptides (I) (somatostatin), (II) (antamanide), (III) (cyclolinopeptide A), (IV) ("PPF"), and (V) ("008") demonstrate that constitution and conformation determine the biological activity of a peptide.
ChemInform Abstract The cyclic hexapeptide (I) contains the retro sequence of the amino acid residues 7-11 of the peptide hormone somatostatin bridged by D-proline; it is about 70 times more active than somatostatin. The conformation of six analogues (II)-(VII) of (I) in which each amino acid is substituted by an Ala or D-Ala residue is studied in detail. The comparison of the activities in the inhibition of the cholate uptake of isolated hepatocytes with the conformations of these peptides leads to the result that the aromatic side chains are important to achieve high activity.
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