Award details

Radical Radiochemistry for Site- and Copy-Controlled 18F-Labeling of Proteins

ReferenceBB/V010999/1
Principal Investigator / Supervisor Professor Benjamin Davis
Co-Investigators /
Co-Supervisors
Professor Veronique Gouverneur, Professor Katherine Vallis
Institution The Rosalind Franklin Institute
DepartmentResearch
Funding typeResearch
Value (£) 845,479
StatusCurrent
TypeResearch Grant
Start date 01/11/2021
End date 19/04/2025
Duration42 months

Abstract

Positron Emission Tomography (PET) captures functional changes associated with biology and pathology. It is now core to diagnosing disease and monitoring how patients respond to therapy but only when relevant radiotracers exist. It also central to drug development but typically mainly applied to small molecules. Methods to allow direct, ready and rapid formation of 'zero-size' equivalents that bear a discreet reporter label that does not perturb function will allow simultaneous: i) direct, artefact ('scar')-free tracking of biomolecule location; ii) direct artefact-free reporting of chosen biomolecule function; iii) precise monitoring of biomolecule utilization and fate. Incorporation of 18F into peptides/proteins is typically achieved by statistical, heterogeneous modifications using linker and/or prosthetic groups or chelating groups 18F labelling. Although adequate - indeed powerful - for many PET studies, the extra 'limb' / 'scar' this creates, combined with poor control over copy number and site-selectivity, can detrimentally affect structure and function. It therefore generates artefacts in analyses that precludes more precise interpretation of PET in Biology and Medicine. To address limitations, direct controlled 18F-labeling is necessary. Each site of labelling creates sources of artefact as it moves away from a native structure but if minimized then artefact can be minimized - this is 'zero-size, zero-background'. In this grant we will develop technology that could broadly impact the community. 1 very similar size & properties mean alteration C-H --> C-F is near-perfect 2) 18F-incorporation will not compromise function ('near' wild-type). 3) methods installing complete 18F-labeled amino acid side-chains would uniquely control labelling 4) fast kinetics will be essential 5) constraints [incl short 18F t1/2 ] rule out normal ribosomal machinery. Solution: Post-translational mutagenesis inserting 18F-labeled side-chains into 18F-proteins

Summary

One of the most common methods for diagnosing and following the development and/or treatment of disease is to use positron emission tomography (PET). This relies upon the use of suitable positron emitting radionuclides: unstable elements that collapse emitting positron radiation that can bee seen inside even whole bodies. Foremost amongst these is the use of 18F and, indeed, most hospitals in the UK (and around the world) are equipped with suitable scanners to allow the detection of 18 F as a label inside patience. To date, the use of 18F, however has been largely restricted to its attachment to small molecule drugs - most licensed 18F-'radiotracers' are small molecules. This is despite the development of some useful experimental methods for attaching 18F onto more complex molecules of interest, including new and next-generation protein drugs (biologics). Most of these current methods, however, introduce bulky additional groups ('scars' - often in many copies) that lead to perturbation of a biomolecule's function and the creation of mixtures. This creates a conundrum: in that whilst we can label these molecules using these older methods, we cannot be sure that they behave in the same way after labelling. This, in turn, creates the possibility of artefacts in the data that are generated that precludes a deeper understanding of how this important class of molecules behaves and stops the application of PET more generally to understand complex biology and physiology. In this proposal we will develop new methods that allow the insertion of 18F into proteins in a 'scar-free' manner to create more pure 18F-proteins. This will enable their use in a form that is essentially near identical to their natural form. This greater purity and precision is likely to provide an important tool that will allow biological and medical sciences to advance and to use this powerful form of imaging much more widely.
Committee Research Committee D (Molecules, cells and industrial biotechnology)
Research TopicsTechnology and Methods Development
Research PriorityX – Research Priority information not available
Research Initiative X - not in an Initiative
Funding SchemeX – not Funded via a specific Funding Scheme
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