| EPSRC Reference: |
EP/X037819/1 |
| Title: |
Investigations into aryl nitriles for protein modification via an untapped mode of reactivity |
| Principal Investigator: |
Baker, Professor JR |
| Other Investigators: |
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| Department: |
Chemistry |
| Organisation: |
UCL |
| Scheme: |
Standard Research |
| Starts: |
01 January 2024 |
Ends: |
31 December 2026 |
Value (£): |
529,598
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| No relevance to Underpinning Sectors |
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Summary on Grant Application Form |
The controlled chemical modification of peptides and proteins is a crucial underpinning technology for a number of rapidly growing areas in chemical biology and the biomedical sciences. Applications include: antibody-drug conjugates (ADCs) and related targeted therapeutics; radiolabelled proteins for imaging; covalent inhibitors in drug discovery; stapled peptides as stabilised therapeutics; and numerous nanoparticle conjugates/other nanotechnologies. The discovery, development or repurposing of chemical reactions to enable the construction of such conjugates in new ways can be a key driving force behind innovations in the area. This is powerfully illustrated by the recent award of the 2022 Nobel Prize in Chemistry for the development of 'Click Chemistry' which has played a key role in dramatically enabling diverse applications.
In this project we are hypothesising that a particular class of reagents, containing a nitrile functional group, could enable new modes of protein modification via an untapped mode of their reactivity, i.e. their reaction with two thiols consecutively. Once we have demonstrated the viability, efficiency and scope of these reactions, we will explore the new opportunities enabled.
A key focus application will be to enable the construction of ADCs, demonstrating that these nitriles offer a unique dynamic mechanistic pathway to highly homogenous, site-selective antibody conjugates. ADCs represent one of the most exciting classes of new targeted anti-cancer therapeutics, with 13 ADCs now having achieved clinical approval. They aim to overcome the limitations of existing chemotherapeutics by delivering the cytotoxic drug specifically to the cancer cells, and thus reducing the side-effects associated with damaging healthy tissue. To maximise the chances for ADCs achieving their therapeutic potential, their design and chemical construction must be improved. As such, the methods developed in this project aim to provide an extremely convenient and efficient approach to carry out the chemical attachment to antibodies in a highly controlled manner. Furthermore, the reagent class we are developing would be the first of a kind in enabling controlled attachment to two different amino-acids on the surface of antibodies simply by tuning the molecular design; by strategies known as 'disulfide stapling' and 'cysteine-to-lysine transfer'. This will also enable us to carry out iterations of controlled chemical modification, accessing multifunctional conjugates which represent an enticing prospect for the next generation of antibody-based therapeutics.
In a second key demonstration of applications enabled by the chemical methods pioneered in this project, we aim to show that nitrile reagents could also offer a unique ability to selectively inhibit specific classes of enzymes. Such covalent inhibitors are a growth area in drug discovery, as they offer the prospect of prolonged therapeutic effects. However, selectivity is vital in such strategies. We aim to show that reagents which form stabilised adducts only when they react with two proximal cysteine amino-acids, form a new mechanistic class of selective inhibitors for enzymes.
Our overall approach within this project is to explore and tune an untapped, fascinating chemical reaction, and to demonstrate that it offers significant new opportunities in protein modification. In so doing, this project will offer insights stretching from fundamental chemistry to therapeutic development.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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