PT  - JOURNAL ARTICLE
AU  - Hanna Harant
AU  - Barbara Wolff
AU  - Erwin P. Schreiner
AU  - Berndt Oberhauser
AU  - Lotte Hofer
AU  - Nicole Lettner
AU  - Sabine Maier
AU  - Jan E. de Vries
AU  - Ivan J. Lindley
TI  - Inhibition of Vascular Endothelial Growth Factor Cotranslational Translocation by the Cyclopeptolide CAM741
AID  - 10.1124/mol.107.034249
DP  - 2007 Jun 01
TA  - Molecular Pharmacology
PG  - 1657--1665
VI  - 71
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/71/6/1657.short
4100  - http://molpharm.aspetjournals.org/content/71/6/1657.full
SO  - Mol Pharmacol2007 Jun 01; 71
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics