Sequence controlled glycopolymers for selective lectin targeting

Carbohydrate binding proteins (CBPs) mediate diverse biological functions such as endocytosis, host-pathogen interactions, cell adhesion & trafficking and intracellular signal transduction. Exact chemical structures of some glycoproteins have already been reported in the literature. However, the chemical synthesis of even a small section of glycoprotein structures are extremely challenging and still may not exhibit the same biological activity in comparison to when they are incorporated into highly sophisticated complete glycoprotein structures. Glycopolymers (GP) have been shown to mimic glycan functions due to their multivalency and ability to bind various CBPs, but they lack CBP specificity. Thus development of systematic GP libraries with precise sequence control, architecture and folding in order to identify their specific binding to human dendritic cell (DC) carbohydrate binding proteins is highly appealing. Highly efficient chemical routes to prepare precision GPs while increasing the diversity in coding by altering carbohydrate type and number per polymer chain, microstructural distribution along the chain, and architecture of the chain will be investigated. Each of these parameters are known to have an enormous effect on specific recognition, binding kinetics and DC signalling.

Sugar code in a human body is a highly complex and well established mechanism, which is responsible of various biological recognition events. The specific recognition of carbohydrate binding proteins on immune system related cells have a critical importance for improved health of humans. This project is concerned with developing a series of synthetic carbohydrate containing macromolecules that can target specific carbohydrate binding proteins on dendritic cells. The development of such a synthetic sugar code would potentially open the doors of precisely specific cell targeted drug delivery to selected cells. Moreover, such glyco structures would induce cell signalling upon interaction with certain lectins that may activate cell proliferation or apoptosis.

The development of a platform for selectively lectin binding macromolecules that can be used in specific cell targeting and stimulate cell signaling will be of immediate interest to the international scientific community and have significant research impact. Moreover, exemplification of the platform using clinically relevant Dendritic Cell binding macromolecules will broaden the impact of the work significantly and across a broad range of fields (e.g. respiratory diseases, infectious diseases, theranostics). The uptake of discoveries is expected to be rapid, especially in the context of the growing number of chemical biology based laboratories and biotechnology companies where precisely targeted drug delivery and inhibitory agents for allergy or infectious diseases play a major role. To ensure maximum impact for science, the results will be widely disseminated. This project has the potential to impact across various subject areas in which glycoproteins, peptides, cell-targeting play a crucial role, e.g. chemistry, biochemistry, biology, bioengineering and medicine.

The pharma industry has clearly acknowledged that a shift from the traditional small molecule drugs to larger multivalent structures and the application of bioactive materials could provide significant future breakthroughs in biomedical materials for example the targeted delivery of highly specific next generation biopharma therapeutics (peptides, proteins, siRNA, etc.). Multivalency is a typical domain of synthetic macromolecules and in combination with biologically active units these so-called biomimetics could re-fill the product funnel if sophisticated synthetic routes and formulation technology is developed. It is now more than evident that glycosylation will play a significant role in the next generation of active pharmaceutical and biomedical products. The majority of the therapeutic proteins approved by the European and US regulatory authorities until 2006 were glycosylated with some 500 candidates at the clinical development stage with an estimated annual market of $ 880 billion. Glycans, i.e. carbohydrates (complex sugars) play an essential role in cell interactions, recognition events, disease states, etc. Virtually all cells are covered with glycans and a majority of naturally occurring proteins is glycosylated. Recent advances in bioanalytical tools reveal the crucial role played by these complex glycans in almost every essential biological process, e.g. reproduction, signaling, cell differentiation, immunity and significant diseases that affect all EU states such as cancer, inflammation, and microbial infection. It is therefore no surprise that many new biopharmaceuticals in development are glycoproteins, glycosylated molecules or have glycoprotein targets.