RT Journal Article
SR Electronic
T1 Inhibition of Vascular Endothelial Growth Factor Cotranslational Translocation by the Cyclopeptolide CAM741
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1657
OP 1665
DO 10.1124/mol.107.034249
VO 71
IS 6
A1 Hanna Harant
A1 Barbara Wolff
A1 Erwin P. Schreiner
A1 Berndt Oberhauser
A1 Lotte Hofer
A1 Nicole Lettner
A1 Sabine Maier
A1 Jan E. de Vries
A1 Ivan J. Lindley
YR 2007
UL http://molpharm.aspetjournals.org/content/71/6/1657.abstract
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