Protein mimics by molecular scaffolding of peptides

Abstract

The research in this thesis aimed at the development of a new route for the synthesis of discontinuous epitope mimics. Mimicry of discontinuous epitopes is often achieved through mounted peptides corresponding to the epitope sequence on a molecular scaffold. In this thesis a new method for the synthesis of these mimics was developed by using sequential introdcution of peptides onto the scaffold using CuAAC chemistry. This resulted in a synthesis method that was convergent, efficient, and easily adaptable. Using this method mimics of epitopes of the Pertussis protein and the gp120 protein were synthesized. The gp120 mimics were able to competitively inhibit the binding of natural gp120 to CD4. Furthermore, the importance of peptide cyclization was investigated. Mimics containing linear peptides were able to inhibit the gp120-CD4 binding but to a somewhat lesser extent. However, the stability in serum of mimics consisting of cyclic peptides was far better than the linear mimics, which shows the benefits of the use of cyclic peptides in protein mimics