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Synthetic receptors for viruses

Surface-imprinted hybrid materials for the selective detection of viruses

Dr. Mehmet Dinc (Hahn-Schickard), Prof. Dr. Boris Mizaikoff (Universität Ulm, Institut für Analytische und Bioanalytische Chemie)

Thanks to technological advances in polymer chemistry and nanotechnology, it is now possible to synthetically produce nanomaterials with a wide range of properties and functionalities. This has paved the way for producing bio-inspired structures and systems which, for example, possess binding properties that follow the molecular recognition principles of biological systems. The variety of synthesis possibilities has stimulated the development of molecularly imprinted polymers (MIPs), which are often referred to as “synthetic receptors” or “biomimetic recognition materials”. Originally conceived for small molecule templates, it has been possible to expand the concept of molecular imprinting, first to biomacromolecules and now to whole cells, bacteria and viruses.

In the pharmaceutical, medical, environmental and food sectors, there is a growing need to detect target substances in complex mixtures efficiently and selectively. This process can help to isolate and/or purify specific targets from complex mixtures, to concentrate a sample for easier subsequent analysis or to deplete and remove impurities. It usually involves several time-consuming and cost-intensive steps using different chromatographic methods or solid phase extractions. To purify and separate biomacromolecules (proteins, DNA, etc.) or even entire viruses (e.g. in the biotechnological production), immobilized antibodies, antigens, enzymes or aptamers are often used as selective recognition elements. The so-called ELISA tests (enzyme-linked immunosorbent assays) used in serological diagnostics are also based on natural receptors and the interactions of these with target substances. Although exceptionally selective, such biological recognition elements are often available only in limited quantities, difficult and expensive to produce and not stable enough under the conditions of some applications. Furthermore, for many important analytes there are no suitable natural receptors available. Effective and rapid recognition, purification or separation could, for example, significantly reduce the production costs of biological species. Molecularly imprinted polymers have the potential to fulfill this essential task.

Synthetically tailored materials for molecular recognition

Fig.1 Schematic illustration of non-covalent and covalent imprinting based on monomer-template interactions during MIP synthesis. Reproduction from [4], with permission from Elsevier

Molecular recognition plays an important role in biochemical processes and tends to be based on interactions between complementary molecules, e.g. receptor-ligand, antibody-antigen, DNA-protein or RNA-ribosome. In biological systems, molecular recognition is typically based on non-covalent interactions, such as hydrogen bonds, coordinative bonds, hydrophobic forces, π-π interactions, van der Waals forces and electrostatic effects. The molecular specificity of such interactions is crucial for the proper biological functioning of biomacromolecules [1]. The concept of molecular imprinting is based on the biomimetic imitation of such molecular interactions for recognition, but with synthetically tailored materials. The template (i.e. the target species, the target molecule, a structural dummy or an epitope) interacts with functional monomers in a suitable solvent. This mixture is subsequently polymerized using a crosslinker to form a highly interlinked, three-dimensional matrix containing the template-molecule complex. Removing the template leaves behind specific “chemical imprints”, both functional and spatial, in the polymer. These are complementary to the template species and thus possess selective binding properties (see Fig. 1). In practice, these processes are highly complex, and some aspects are not yet fully understood [2-3].

MIPs are typically produced as monoliths by block copolymerization. This technique has several disadvantages, such as a low number of near-surface binding sites or irregularly shaped particles after comminution. Especially the imprinting of biomacromolecules with their high molecular weights (e.g. peptides, proteins, DNA, viruses, bacteria) is a considerable challenge due to the dimensions involved, the limited solubility and stability in commonly used organic solvents, the complex structures, slow mass transport and structural flexibility.

Hybrid materials for innovative syntheses and applications

Triggered by advances in polymer chemistry and nanotechnology, core-shell imprinting has become a frequently used technique in recent years. It is particularly suitable for imprinting biomacromolecules. The basic strategy is to create binding sites at or near the surface of the structural core material to allow unhindered access to the binding sites even for large molecules or entire biospecies. Inorganic core materials such as silica particles, magnetic nanoparticles, quantum dots and gold nanoparticles are particularly suitable for this purpose due to their adjustable geometries and surface properties. They are subsequently coated with a nano-thin, imprinted polymer layer. The main advantage of so-called inorganic-organic hybrid materials is that they combine the desired chemical and physical properties of organic and inorganic materials in their final structure and, because of the diversity of materials that can be used, open up possibilities for innovative syntheses and applications. Using silica particles has become customary for producing molecularly imprinted hybrid materials, due mainly to their chemical stability under acidic conditions, their biocompatibility, their dispersibility in aqueous media as well as their flexible physical and chemical properties [4].

Inhibitor-assisted synthesis for greater selectivity and binding capacities

Fig. 2 Inhibitor-assisted synthesis of surface-imprinted hybrid particles for biomacromolecules

In cooperation with Labor Dr. Merk & Kollegen GmbH and as part of the PROTSCAV I&II projects funded by the German Federal Ministry of Education and Research (BMBF), Boris Mizaikoff's team at the Institute of Analytical and Bioanalytical Chemistry (IABC; uni-ulm.de/en/nawi/iabc) at Ulm University has established the so-called inhibitor-assisted synthesis of surface-imprinted silica particles to selectively bind proteases [5-6]. The inhibitor’s function is to endow the template molecule with a defined orientation on the surface of the particles prior to the imprinting process, so the binding sites that remain on the nano-thin polymer layer after removing the template are more homogenous (see Fig. 2). Binding studies have shown that this innovative technique significantly increases both selectivity and binding capacity. It has been successfully used, for example, to selectively separate the metalloproteases MMP9 and MMP12 in cell culture supernatants [7].

First visualization of viruses binding to MIP particles

This concept has been further developed at the IABC in order to selectively bind entire viruses using surface-imprinted hybrid materials. In times of SARS-CoV-2, the analysis of viruses and their selective detection has unexpectedly gained importance, in addition to the ever more frequent occurrence of virus variants and resistances [8]. Even before the corona pandemic, the IABC had used biomimetic materials to successfully develop imprinting strategies for the selective binding of a virus, the human adenovirus type 5 responsible for 5 to 10 % of respiratory tract infections [9]. In another first, it could be shown that the addition of bovine serum albumin largely suppresses non-specific interactions [10]. These studies were also the first to visualize viruses actually binding to MIP particles by means of super-resolution STED (stimulated emission depletion) fluorescence microscopy [11].

Developments and outlook

To enable virus imprinting under normal laboratory conditions without having to use pathogenic templates, a so-called epitope approach has been developed. Only by imprinting the hexon protein, the essential viral capsid protein component of the human adenovirus type 5, could the entire virus be selectively detected in competitive binding studies [12]. In ongoing research at the IABC and Hahn-Schickard, these technologies are being adapted for use on other relevant viruses, including SARS-CoV-2 and Zika.


Category: Bioanalytics | Molecularly Imprinted Polymers

[1] Chen, W., Tian, X., He, W., Li, J., Feng, Y., Pan, G. (2020), Emerging functional materials based on chemically designed molecular recognition, BMC Mater., vol. 2, no. 1, 1–22, DOI: 10.1186/s42833-019-0007-1
[2] Zink, S., Moura, F. A., Autreto, P. A. D. S., Galvão, D. S., Mizaikoff, B. (2018) Efficient prediction of suitable functional monomers for molecular imprinting: Via local density of states calculations, Phys. Chem. Chem. Phys., vol. 20, no. 19, 13153–13158, DOI: 10.1039/C7CP08283E
[3] Zink, S., Moura, F. A., Autreto, P. A. D. S., Galvão, D. S., Mizaikoff, B. (2018) Virtually imprinted polymers (VIPs): Understanding molecularly templated materials: Via molecular dynamics simulations, Phys. Chem. Chem. Phys., vol. 20, no. 19, 13145–13152, DOI: 10.1039/c7cp08284c
[4] Dinc, M., Esen, C., Mizaikoff, B. (2019) Recent advances on core-shell magnetic molecularly imprinted polymers for biomacromolecules, TrAC - Trends Anal. Chem., vol. 114, 202–217, DOI: 10.1016/j.trac.2019.03.008
[5] Dinc, M. et al. (2018) Selective Binding of Inhibitor-Assisted Surface-Imprinted Core / Shell Microbeads in Protein Mixtures, ChemistrySelect, vol. 3, 4277–4282, DOI: 10.1002/slct.201800129
[6] Dinc, M., Basan, H., Diemant, T., Behm, R. J., Lindén, M., Mizaikoff, B. (2016) Inhibitor-Assisted Synthesis of Silica-Core Microbeads with Pepsin-Imprinted Nanoshells, J. Mater. Chem. B, 4462–4469, DOI: 10.1039/C6TB00147E
[7] Schauer, N. et al. (2018) Selective binding of matrix metalloproteases MMP-9 and MMP-12 to inhibitor-assisted thermolysin-imprinted beads, RSC Adv., vol. 8, no. 57, 32387–32394, DOI: 10.1039/C8RA04444A
[8] Gast, M., Sobek, H., Mizaikoff, B. (2019) Advances in imprinting strategies for selective virus recognition a review, TrAC - Trends Anal. Chem., vol. 114, 218–232, DOI: 10.1016/j.trac.2019.03.010
[10] Gast, M., Kühner, S., Sobek, H., Walther, P., Mizaikoff, B. (2018) Enhanced Selectivity by Passivation: Molecular Imprints for Viruses with Exceptional Binding Properties, Anal. Chem., vol. 90, no. 9, 5576–5585, DOI: 10.1021/acs.analchem.7b05148
[11] Gast, M., Wondany, F., Raabe, B., Michaelis, J., Sobek, H., Mizaikoff, B. (2020) Use of Super-Resolution Optical Microscopy to Reveal Direct Virus Binding at Hybrid Core-Shell Matrixes, Anal. Chem., vol. 92, no. 4, 3050–3057, DOI: 10.1021/acs.analchem.9b04328
[12] Gast, M., Sobek, H., Mizaikoff, B. (2019) Selective virus capture via hexon imprinting, Mater. Sci. Eng. C, vol. 99, no. November 2018, 1099–1104, DOI: 10.1016/j.msec.2019.02.037

Date of publication: 24-Jul-2020

Facts, background information, dossiers

  • molecularly imprint…
  • synthetic receptors
  • hybrid materials
  • core-shell imprinting
  • silica particles
  • magnetic nanoparticles
  • inhibitor-assisted…
  • biomimetic materials
  • stimulated emission…
  • epitopes
  • viruses
  • SARS-CoV-2

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  • Authors

    Prof. Dr. Boris Mizaikoff

    Boris Mizaikoff, born in 1965, received his doctorate in analytical chemistry from the Vienna University of Technology (Austria) in 1996 and qualified as a professor with tenure at the Vienna University of Technology in 2000. Subsequently, he worked at the Georgia Institute of Technology (A ... more

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