Comparative analysis of HER2 specific oligopeptides: investigating receptor-peptide interactions and structures
The HER2 receptor is overexpressed in 15-30% of breast cancers, it decreases the overall survival of patients and elevates the occurrence of metastases. There are several HER2 targeting monoclonal antibodies and inhibitors in therapeutic use, however, high percentage of patients shows resistance against them.
In targeted tumor therapy, the use of tumor targeting peptides has increased: their easy synthesis and the beneficial pharmaciokinetical properties make them good candidates for both diagnostical and therapeutic use. Among the HER2 binding oligopeptides investigated by the MTA-ELTE Research Group of Peptide Chemistry, oligopeptide P1 showed the most specific and highest binding to receptors of HER2 overexpressing breast cancer cells.
The amino acid sequence of oligopeptide P1 is highly similar to one of the receptor binding part of a HER2 binding antibody mimetic Affibody molecule. Moreover, secondary structure prediction estimated that the P1 peptide has the highest alpha-helical content and its degree is related to the specificity of the peptide. Therefore, we also designed Affibody variants that contain the sequence of the P1 peptide.
The first step of our common work is the synthesis of proteins (HER2, Affibody and its variants) and oligopeptides. Our next aim is to determine the binding affinity, the interaction surface and the 3D structure of the complex. This knowledge serves as a basis for further sequence optimization and affinity enhancement. Besides, our goal is to optimize the synthesis and purification of the highly stable Affibody molecule (bioreactor – increase of biosynthetic capacity), determine the structural properties and dynamics of the complex (ECD spectroscopy, NMR).
The synergic work between the two MTA-ELTE reserach groups has double goal. On the one hand, our aim is to prepare specific binding peptides by investigating protein-peptide interaction and structure that can be used in diagnostics or as a drug targeting tool in the future. On the other hand, our plan is to use the received results and experience to study further receptor-peptide interactions (new type of diagnostics, structure optimization of peptide based drug conjugates).
Beáta Biri-Kovács, Ildikó Szabó, Pál Stráner