CELLMULTIVINT · Combining supramolecular chemistry, physico-chemical characterization and theoretical modeling to understand multivalent interactions at the cell-hyaluronan matrix interface""

Combining supramolecular chemistry, physico-chemical characterization and theoretical modeling to understand multivalent interactions at the cell-hyaluronan matrix interface

Fifteen years ago, Mammen et al. highlighted the ubiquity and importance of multivalent interactions in biological systems (Angew. Chem. Int. Ed. 1998, 37:2754). However, after over 500 citations, only few experimental studies have addressed the complexity of multivalent binding to surfaces. The reason for this shortcoming is principally due to the bottleneck in reaching good specificity (absence of non-specific binding to surfaces), good experimental control (e.g. over binding strength between the individual ligands and receptors, or over amount of binders on nanoobjects) and tunability (e.g. of density of surface binding sites). In this project, we have developed well-defined, highly specific and tunable model systems to study multivalent binding of polymers and proteins to functional surfaces. Using this experimental platform, we provided the first direct experimental evidence for superselectivity in the multivalent binding to surfaces (Dubacheva et al, J. Am. Chem. Soc. 2014, 136:1722). Superselectivity means that the surface density of bound objects increases faster than linearly with the density of binding sites on the surface. Using analytical modelling, we showed that superselectivity i) is indeed a consequence of multivalency and ii) is enhanced by the ability of polymers to interpenetrate, a unique feature in comparison with other multivalent scaffolds such as particles. Furthermore, we provided the first direct experimental demonstration that superselective binding can be tuned through the design of a multivalent probe to specifically target a desired surface density of binding sites (Dubacheva et al, Proc. Natl. Acad. Sci. USA, 2015, 112:5579). By combining data from a quantitatively tuneable experimental model system with analytical modelling and simulations, we arrived at a coherent picture of the molecular determinants of superselective binding. The developed analytical model provides, in a simple way, quantitative predictions of how molecular characteristics such as size, valency and affinity affect superselective binding, and hence facilitates the design of functional multivalent probes. This work provides mechanistic understanding of multivalent binding to surfaces, and lays the foundation for the rational design of multivalent probes for superselective targeting under specific biological conditions. The obtained results demonstrate that, due to superselectivity and tuneability, multivalent polymers have the potential to serve as versatile probes in biomedical applications, such as the design of polymeric drugs for selective cell targeting. Given the diversity of multivalent scaffolds which have been recently developed for numerous biomedical applications (Angew. Chem. Int. Ed. 2012, 51, 10472; Biomacromolecules 2015, 16:43), our approach opens up a route for future developments in other fields of nano-medicine, including modulation of cell signalling, toxin and pathogen inhibition, and immune modulation. Besides, this work also makes an important step towards the understanding of naturally occurring multivalent interactions such as between the extracellular matrix polysaccharide hyaluronan and cell surfaces.

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