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Molecular Pharmacology Fast Forward
First published on March 16, 2007; DOI: 10.1124/mol.107.034249

0026-895X/07/7106-1657-1665$20.00
Mol Pharmacol 71:1657-1665, 2007

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Inhibition of Vascular Endothelial Growth Factor Cotranslational Translocation by the Cyclopeptolide CAM741

Hanna Harant, Barbara Wolff, Erwin P. Schreiner, Berndt Oberhauser, Lotte Hofer, Nicole Lettner, Sabine Maier, Jan E. de Vries, and Ivan J. Lindley

Novartis Institutes for BioMedical Research, Vienna, Austria

The cyclopeptolide CAM741 inhibits cotranslational translocation of vascular cell adhesion molecule 1 (VCAM1), which is dependent on its signal peptide. We now describe the identification of the signal peptide of vascular endothelial growth factor (VEGF) as the second target of CAM741. The mechanism by which the compound inhibits translocation of VEGF is very similar or identical to that of VCAM1, although the signal peptides share no obvious sequence similarities. By mutagenesis of the VEGF signal peptide, two important regions, located in the N-terminal and hydrophobic segments, were identified as critical for compound sensitivity. CAM741 alters positioning of the VEGF signal peptide at the translocon, and increasing hydrophobicity in the h-region reduces compound sensitivity and causes a different, possibly more efficient, interaction with the translocon. Although CAM741 is effective against translocation of both VEGF and VCAM1, the derivative NFI028 is able to inhibit only VCAM1, suggesting that chemical derivatization can alter not only potency, but also the specificity of the compounds.

Received for publication January 19, 2007.

Accepted for publication March 16, 2007.

Address correspondence to: Hanna Harant, Novartis Institutes for BioMedical Research, Brunner Strasse 59, A-1235 Vienna, Austria. E-mail: hanna.harant{at}novartis.com






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