Adaptive Artificial Receptors for Biomimetic Functions

Over the past few decades, chemists have developed very efficient methods for making molecular containers from simple building blocks. These molecular containers are of great interest as chemists have shown that the hollow cavity within their centre can be used to capture a wide range of guest molecules on the inside the container. Chemists often choose to capture guest molecules with biological relevance as these systems then have the potential to then be used for medical applications; for example to treat diseases within our bodies, e.g. for capturing anticancer drug molecules with long-term potential uses in the treatment of cancer or for the sensing of sugar molecules which holds potential applications in diagnosing and management of diabetes. However, one of the major drawbacks of many existing molecular containers is that because they are made from rigid artificial building blocks, these inflexible molecular containers are unable to display responsive behaviour. As a result, the rigid molecules containers, unlike biological systems, are not able to adapt to the changes in environment and, instead of being able to treat a disease at a specific site within our bodies, they will interact with different molecules within our bodies and lose their ability to effectively treat the disease at its source. Therefore, in order to make full use of the potential of these molecular containers for medical applications within our bodies (for example sugar sensing and anticancer treatments) we need to make sure that they can interact with only the desired guest molecule (be that a sugar or drug molecule) and not with all the other undesired components and molecules within our bodies.

The proposed research addresses this problem associated with existing rigid molecular containers and describes the development of a new type of molecular container that uses flexible building blocks made from biologically inspired components. These new molecular containers have specific sites incorporated into their central cavity which allows them to be able to selectively interact with the one desired guest molecule from a large mixture of guest molecules. The ability of these flexible molecular containers to selectively interact with one molecule in a complex mixture of molecules is inspired by the "lock-and-key" mechanisms used by many biological systems. Moreover, the flexible nature of the biologically inspired building blocks also allows these new molecular containers to undergo controlled changes in their shape so that they can completely break apart in order to release the guest molecule from the central cavity in a controlled manner when desired. This responsive behaviour of the molecular container, for the controlled capture and release of one specific and desired guest molecule (for example an anti-cancer drug molecule) even in the presence of large numbers of other undesired guest molecules, means that they have the potential to adapt to the complicated environments found within our bodies. As a result of this responsive behaviour, these new flexible molecular containers have the potential to be used for biomedical applications e.g. capturing an anticancer drug molecule, transporting it to the site of tumour within our bodies and then releasing the anticancer drug at the tumour site in order to treat the disease in a more efficient manner than current anti-cancer treatments.

The development of these new molecular containers, which contain flexible biological building blocks, that are able to adapt to interact with one desired guest molecule from a complex mixture, have a clear advantage over many existing ones as they have the striking potential to carry out medical applications within our bodies, for example the sensing of a sugar molecule or deliver an anticancer drug to a tumour site.

The research proposal outlines the creation of novel adaptive artificial receptors with the ability to demonstrate adaptive behaviour which can be exploited to carry out important biomimetic functions such as sugar sensing, small molecule delivery (of pharmaceutical active ingredients) or acting as catalysts to induce enantiomeric excess in reactions.

The fundamental studies detailed in this Fellowship proposal, describing the self-assembly of novel receptors from biomimetic building blocks will impact other researchers working at the interface of chemistry and biology, particularly chemical biologists, synthetic organic and inorganic chemists and supramolecular chemists. The fundamental data that will be acquired from these investigations will be of direct interest to other researchers in different disciplines working within the Systems Chemistry: Exploring the Chemical Roots of Biological Organisation Grand Challenge of the EPSRC. The outlined development of hybrid organic-inorganic systems will directly impact synthetic researchers working within both fields whilst the proposed binding studies to investigate the nature and strength of the host-guest chemistry of the systems will provide a wealth of information for physical organic chemists. The 2009 International Review of Chemistry recognised supramolecular chemistry as a national strength but it identified that "the influence of modern physical chemistry on the field of supramolecular chemistry is lagging behind other nations." The physical organic studies outlined in this proposal will facilitate the competiveness of the UK in this field of research.

The researchers (PDRA and PhD) will be direct beneficiaries of the Fellowship. The research programme will directly impact on their professional training and will develop the synthetic organic and inorganic skills of the PDRA and PhD student and also progress their time management skills for the successful progression of research projects. The PDRA and PhD student will be given the opportunity to attend training courses to improve employability skills and they will have the potential to contribute to the UK economy through engaging in posts in teaching, industry or academia.

Communication of results to the scientific community will be undertaken through publication of the research findings in high-profile, international journals with high-impact factors. Presentation of the results at national and international conferences will be sought including general chemistry (e.g. Dalton Meetings) and more specific supramolecular chemistry conferences. To communicate with academics in related fields who could benefit from the research (e.g. biological chemists) membership to other RSC groups e.g. Peptide and Protein Science Groups will be undertaken. To inform the general public of the research being undertaken, a range of publicity and media releases will be employed.

The development of responsive drug-delivery systems has the long-term potential to treat cancer at the tumour site within a body and this could impact a wide-range of researchers including biological chemists pharmacists and biomedical scientists. The potential long-term use of the receptors for the healthcare related applications of anti-cancer drug delivery at tumour sites and sugar sensing could indirectly impact on health researchers and those working within this sector.