Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Inhibition of vascular endothelial growth factor cotranslational translocation by the cyclopeptolide CAM741.

Harant, Hanna and Wolff-Winiski, Barbara and Schreiner, Erwin and Oberhauser, Berndt and Hofer, Lotte and Lettner, Nicole and Maier, Sabine and De Vries, Jan Egbert and Lindley, Ivan-J.D. (2007) Inhibition of vascular endothelial growth factor cotranslational translocation by the cyclopeptolide CAM741. Molecular Pharmacology, 71 (6). pp. 1657-1665. ISSN 0026-895X

Abstract

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.

Item Type: Article
Related URLs:
Additional Information: author cannot archive post-print (ie final draft post-refereeing)
Related URLs:
Date Deposited: 14 Dec 2009 13:59
Last Modified: 31 Jan 2013 01:16
URI: https://oak.novartis.com/id/eprint/457

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.