Tetra-(Polyfluoroaryl)-Porphyrin Templated Multicyclic Peptides: Novel, Functional and Responsive Scaffolds for Miniaturised Biosensors

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This First Grant will help to establish a new multidisciplinary 'chemical biology' team within the School of Pharmacy and Biomolecular Sciences at Liverpool John Moores University, UK, focused on using peptide and fluorine chemistry to interrogate biological problems e.g. enzyme mechanisms and disease diagnosis. Individuals are increasingly interested in knowing more about their health and ways to improve it through changes in diet or exercise, with tests available to determine the risk of developing a disease. Early detection of abnormalities in a sample (e.g. blood), can help diagnose diseases; however, patients are often not aware they are ill or at risk, which results in late diagnosis and treatment. Developing new technologies to allow early diagnosis and screen people for the invisible tell-tale signs of disease is, therefore, important as this will impact on a) health-screening services which are becoming a rapidly growing business worldwide, and b) for the NHS to reduce the cost of treatment and to help people live longer, healthier lives in the UK.Our immune system produces specific antibodies during disease, which can also be used to diagnose disease in lab tests. However, antibodies outside the body do not survive long, especially in warm environments. This makes testing unstable, expensive and requires chemicals to visualise the disease-causing molecule or organism. This creates transport and storage problems for testing kits, especially in the developing world, where testing for Ebola and Zika viruses (amongst others) and drug-resistance bacteria are a concern.New chemistry approaches have started to be developed, which make 'miniature antibodies' that will fluoresce a different colour when they find the disease-causing agent. Miniaturised antibodies, called multicyclic peptides are a significant advance over existing technologies, since they are: a) more stable to temperature and bodily fluids (last longer), b) 100-times smaller than antibodies (can get places that antibodies can't reach), c) cheaper to manufacture, d) conceptually designable to target any cause of disease, e) will not require additional chemicals to visualise the cause; f) the same shape as antibodies and made from the same building blocks, and so, look the same to e.g. bacteria.The project will:a) First make a group of peptides, which will share some of the same important features of an antibody for recognising disease-causing agents. Advantageously, these can be purposely designed and made rapidly compared with producing antibodies. However, at this stage, they are not the correct shape to recognise a 'target'.b) Optimise methods to attach these to a fluorescent 'template' (polyfluoroaryl-porphyrin) to hold it in the correct shape to appear to be the same as a much larger and more complex antibody. c) Finally, we will measure properties of the 'miniature antibodies', including how bright it fluoresces under UV light, how long it survives e.g. in blood or at higher temperature, and use techniques to see what shape it is i.e. how similar it is to an antibody. Through partnering with a UK biotechnology company, we will conduct some preliminary work to understand how these can be used to detect, for example, antibiotic-resistant 'superbugs' or the Clostridium difficile toxin - a major cause of hospital-acquired illness.In future, we envisage that these new miniature antibodies will be used in testing kits that can be used for health screening at home, in the developing world, hospitals and in research labs around the world.