Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention^{1, 2, 3}. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.

1. Novartis Institutes for BioMedical Research, Brunner Strasse 59, A-1235 Vienna, Austria
2. †Present addresses: Inserm Transfert SA, 18, avenue Mozart, BP172, F-13276 Marseille Cedex 09, France (C.D.-N.); Carl Zwilling Parz-G 1186/1, A-2340 Mödling, Austria (J.B.);Vogelsang 7A, D-38118 Braunschweig, Germany (K.M.)
3. *These authors contributed equally to this work

Correspondence to: Jan E. de Vries¹ Correspondence and requests for materials should be addressed to J.E.d.V. (Email: jan.devries@novartis.com).

Received 31 January 2005; Accepted 18 April 2005

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