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Synthetic Superantibodies – Bioinspired Engineering of Artificial Receptor Structures

Final Report Summary - SUPERANTIBODIES (Synthetic Superantibodies - Bioinspired Engineering of Artificial Receptor Structures)

Molecular recognition is the key phenomenon that forms the basis of almost all biological processes. At the same time, molecular recognition is a phenomenon of prime usability and therefore, from the technical point of view, one of the most important and most widely exploited biological principles. The project addressed the contemporary challenge to develop synthetic receptors, which parallel the favourable characteristics of biomolecular interactions and approach the affinity and specificity that is achieved by nature. At the intersection of molecular biotechnology and materials science, the project provided an innovative scientific and experimental concept to transfer biomolecular recognition into non-biological materials, with a unique potential to outperform the capacity of the biological counterparts.

Biomolecular interactions are characterised by a high affinity and high specificity that yet seems to be unachievable with synthetic materials. A role model for high-affinity, high-specificity biomolecular interaction is the unparalleled capacity of antibodies, and the hybridoma technique invented 1975 by Köhler and Milstein (1984 Nobel Prize in Physiology or Medicine) allows the generation of monoclonal antibodies against almost any substance. Hence, it is not surprising that affinity reagents used in basic research, biosensing, clinical diagnostics as well as for isolation and extraction purposes are nowadays almost entirely dependent on antibodies to achieve the required selectivity and binding strength. Judging by biotechnological standards, however, antibodies have inherent characteristics that limit their applications. As they are large (150 kDa) and complex proteins, the recombinant expression and / or manipulation is complicated and the product exhibits a lack of stability. The use of antibodies as affinity reagents is notoriously expensive, and due their fragility and labile nature they are usually suitable for single use only.

The generation of artificial affinity reagents with characteristics similar to those of antibodies, particularly high specificity, affinity and versatility, is therefore of prime interest to modern biotechnological research and development. Tremendous efforts are being made concerning the biomolecular engineering of antibodies and antibody-like structures to obtain tailored proteins with improved characteristics. These approaches are essentially based on the genetic manipulation of protein scaffolds with natural ligand-binding properties. In addition to such proteinacious receptors, the strong demand for fully synthetic affinity reagents with economical preparation, physical and chemical stability has furthered the development of a new class of artificial recognition elements: namely the molecularly imprinted polymers (MIPs).

The project 'Superantibodies' encompasses an interdisciplinary approach to accomplish the first instance of a biohybrid, yet fully synthetic three-dimensional recognition element by converging the benefits of natural biorecognition with those of a synthetic approach. The bio-inspired concept is modelled on the antibody binding site, whose binding capacity is the result of a defined three-dimensional structure in which loops of polypeptides cooperatively interact with the antigen through specific biomolecular interactions. The project implements a combination of modern biomolecular and bioanalytical techniques to identify peptides within these structures that are pivotal for the interaction with the antigen, and to use organic chemistry to synthetically mimic these peptides whilst maintaining their biological function. Affinity driven self-assembly between these peptides and their specific antigen is used to produce templates for a subsequent molecular imprinting process, resulting in a site-specific integration of peptides into the structural backbone of a molecularly imprinted polymer.