The rational design of TAP inhibitors using peptide substrate modifications and peptidomimetics

✍ Scribed by Monique Grommé; Richard van der Valk; Karen Sliedregt; Leen Vernie; Rob Liskamp; Günter Hämmerling; Jens-Oliver Koopmann; Frank Momburg; Jacques Neefjes

• Book ID: 102827463
• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 746 KB
• Volume: 27
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/eji.1830270415

✦ Synopsis

Abstract

The major histocompatibility complex (MHC)‐encoded transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the lumen of the endoplasmic reticulum. This step precedes the binding of peptides to MHC class I molecules and is essential for cell surface expression of the MHC class I/peptide complex. TAP has a broad sequence specificity and a preference for peptides of around 9 amino acids. To synthesize inhibitors for TAP, we studied various alterations of the peptide substrate. The results indicate that TAP is stereospecific and that peptide bonds engineered into isosteric structures can improve translocation of the peptide. Furthermore, TAP is able to translocate peptides with large side chains that correspond to a peptide of ∼ 21 amino acids in extended conformation. Peptides with longer side chains compete for the peptide binding site of TAP but fail to be translocated. Therefore, they represent the first rationally designed inhibitors of TAP.