Bioorthogonal Bond Cleavage Reactions for Traceless Activation of Drugs and Proteins
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
Bioorthogonal reactions are an attractive area of research in chemical biology. Bond cleavage reactions are being studied as a way to deprotect and therefore activate a protein or a drug with spatiotemporal control. Methods for the release of primary and secondary amines have been established, however strategies for release of tertiary amines need to be developed. There are many examples of drugs that contain a tertiary amine including anticancer (auristatin or tubulysin) and antibiotic (rifabutin or clindamycin) drugs. During this project we will develop a new bioorthogonal method for the traceless release of tertiary amines which can be used to achieve spatiotemporal deprotection of these drugs. This new tool will be invaluable in chemical biology and molecular medicine.
1-(vinyloxy)butyl will be used as a new handle that, when reacted with a tetrazine, will trigger an intramolecular cascade reaction and lead to the release of the tertiary amine. The handle will be installed onto a simple amine (N,N-dimethylbenzylamine) to form a model system which can be used to study the stability of the handle and the kinetics of the tetrazine decaging reaction. The handle will then be attached to several drugs and the stability and release of these prodrugs will be studied in vitro. We will apply the tetrazine decagine methodology that has been developed in the Bernardes group.
1-(vinyloxy)butyl will be used as a new handle that, when reacted with a tetrazine, will trigger an intramolecular cascade reaction and lead to the release of the tertiary amine. The handle will be installed onto a simple amine (N,N-dimethylbenzylamine) to form a model system which can be used to study the stability of the handle and the kinetics of the tetrazine decaging reaction. The handle will then be attached to several drugs and the stability and release of these prodrugs will be studied in vitro. We will apply the tetrazine decagine methodology that has been developed in the Bernardes group.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509620/1 | 01/10/2016 | 30/09/2022 | |||
| 1800475 | Studentship | EP/N509620/1 | 01/10/2016 | 31/03/2020 | Sarah Davies |
| Description | The development of novel chemical protecting groups for masking the activity of drugs has been achieved. These inactive drug molecules can then be selectively activated upon addition of a chemical trigger. This provides a useful strategy for controlling the activation of drugs. Work was done to develop new methodology that increases the scope of drugs that can be protected. Specifically, novel trans-cyclooctene linkers were designed, synthesised and used to protect drugs containing an alcohol or carboxylic acid functionality. Upon addition of a small molecule tetrazine trigger the active drug was released. The kinetics and reaction profiles of the new reactions were studied. Finally, the controlled activation of an anti-inflammatory drug and an antibacterial drug was demonstrated in live cells. |
| Exploitation Route | This strategy can be applied to targeted drug delivery. By administering an inactive drug that was selectively activated at the target site, unwanted side effects that result from off-target interactions with healthy cells would be avoided. Therefore, this would allow higher doses of a drug to be administered, increasing the therapeutic potential of existing drugs. Before this can be acheived, further work is required to optimise the efficiency of the activation strategy and the pharmacokinetics of the protected drug and chemical trigger. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |