Diversity-Oriented Synthesis of Stapled Peptides

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

The pharmaceutical industry has historically had great success in developing therapeutics against targets such as enzymes and receptor proteins. Recent years have witnessed a shift towards exploring new and more challenging biological targets. Protein-protein interactions (PPIs) represent an incredibly rich source of new potential drug targets, as they are irrefutably linked to human diseases, including various cancers. Unfortunately, PPIs remain a large and underexploited class of drug-targets as traditional small molecule approaches are often not ideal for inhibiting PPI interfaces. Conformationally-constrained peptides (often referred to as 'stapled peptides') has emerged as a promising strategy to address these historically 'undruggable' targets and provide new and valuable insights into the complex mechanisms that underlie many diseases with high unmet medical needs.

This proposal aims to develop a new enabling platform for the efficient production of diverse conformationally-constrained peptides with tailored properties that are directly relevant to the pharmaceutical industry. The technique will be exceptional in its efficiency, adaptability and simplicity of implementation, and would represent a major step-change from current chemistry approaches to access constrained peptides with specific chemical/biological profiles. The proposed work has the potential to define a general strategy for the rapid discovery and optimisation of next-generation cancer therapeutics, and deliver a vast array of new high-quality probes for chemical biology studies.

Planned Impact

The impact of this research programme arises from the development of a new enabling platform for the efficient production of diverse conformationally-constrained peptides (often referred to as 'stapled peptides') with tailored properties. This would represent a major step-change from chemists' current approaches to access constrained peptides with specific chemical/biological profiles. Our technology will help define a general strategy for the rapid discovery and optimisation of inhibitors of intracellular and extracellular protein-protein interactions (PPIs) that cannot be functionally modulated by existing modalities. Many PPIs have been irrefutably linked to human diseases, including various cancers, but they remain a large and underexploited class of drug-targets. Furthermore, our platform will deliver a vast array of new, high-quality chemical probes for use in chemical biology applications. This will enhance understanding of PPI networks and the therapeutic potential associated with their inhibition.

Who might benefit from this research? How might they benefit from this research?

Academic community - researchers will benefit from the new synthesis methods and chemical tools that we will invent. We will create a toolbox of different staples for peptide macrocyclisation (so-called 'peptide stapling') that impact distinct biological or chemical properties on constrained peptides. This will benefit other academic researchers by providing them with ready access to new constrained peptide derivatives with specific properties that can be used to address a broad range of problems in medicinal chemistry, chemical biology and the life sciences, and will therefore act as a focal point for chemistry driven multi-disciplinary ventures.

Industry - The research will facilitate changes in the mindsets of medicinal chemists, demonstrating that: (i) constrained peptides should be considered to be attractive drug leads, even for intracellular targets and, (ii) PPIs are generally druggable targets with constrained peptides. This will open up a huge untapped opportunity of potential targets for the pharmaceutical industry. Constrained peptide-based PPI inhibitors agents would have a high level of therapeutic novelty and a significant market impact. The modular format of our synthesis platform will enable the rapid optimization of target binding and therapeutic profiles towards any given PPI, thus expediting the "molecule to man" transition.

General Public - Improvements to health and quality of life are potential impacts of the research in this proposal, and while these benefits will primarily be seen through new and improved medicines, we will make every effort to communicate the fundamental breakthroughs we make to the general public.

Education - We will influence the education of chemistry students. The therapeutic value of constrained peptides and PPI inhibition is being taught to students and will make its way into online teaching materials and textbooks providing high value impact in education.

Economy - There are many potential benefits to the UK economy that stem from applications of this research. For example, it will provide a highly skilled and educated workforce, boosting the knowledge base and hence economic output of the chemical industry. I am at the stage in my career where many top quality researchers apply to work in my laboratory and many of them will secure fellowships from their home countries. Therefore the Fellowship extension will provide leverage to access further funding from other agencies, providing high value for money to EPSRC.

Publications

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Bargh JD (2020) Sulfatase-cleavable linkers for antibody-drug conjugates. in Chemical science

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Brear P (2018) Novel non-ATP competitive small molecules targeting the CK2 a/ß interface. in Bioorganic & medicinal chemistry

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Counsell AJ (2020) Efficient and selective antibody modification with functionalised divinyltriazines. in Organic & biomolecular chemistry

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Curran P (2019) Hotspots API : a toolkit for the application of fragment hotspot mapping to structure-based drug discovery in Acta Crystallographica Section A Foundations and Advances

 
Description There are several developments achieved through this award, including advances in stapling peptides and modifying biomolecules, and understanding of protein-protein interaction modulation.

For example, a key discovery has been the use of divinyl-pyrimidines to rebridge disulphide bonds. Disulphides are used commonly in proteins to maintain their structural integrity. We can retain this property, but add a handle to this linkage for further manipulation. A key application for this is to generate next generation antibody drug conjugates.

Antibody-drug conjugates (ADCs) are an important new therapeutic modality in the fight against cancer. ADCs can be likened to a 'magic bullet'; they use an antibody that recognises a cancer cell surface protein to specifically deliver a highly toxic payload, killing the malignant cells while limiting exposure to healthy tissue. However, there remains a number of significant issues with the core ADC components, in particular the linker portion, which if overcome would make this modality more widely applicable. Improved linker technologies would be a step forward to improve the stability of the therapeutic, reduce toxicity, and improve manufacture (no need for antibody (Ab) engineering and consistent drug dosing).

The Spring group, with Cambridge Enterprise and AstraZeneca, has recently developed and filed a patent (WO Application No: PCT/EP2018/070703) on a revolutionary, novel linker technology. We have developed a linker that in the lab can achieve all of the improvements listed above, but further testing is required within living biological systems to demonstrate its therapeutic applicability in order to secure commercialisation.
Exploitation Route There are a number of companies developing ADCs and whilst the specificity of the antibody and toxicity of the warhead are important, the linker part of the molecule is also crucial for clinical success. Despite hundreds of trials, only 4 ADCs have been approved by the FDA, the lack of success has been attributed to poor linker stability resulting in release of the toxin before the drug has reached the necessary cancer cell leading to off-target side effects. Recent ADC failures include Sanofi's anti-LAMP1 drug SAR428926, ADC Therapeutics breast cancer drug ADCT-502 and AbbVie's ADC cancer therapy SC-007.

Our linker technology overcomes the critical stability hurdle. We believe that the pharmaceutical industry will be keen to use our technology in their drugs of the future.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description The work has lead to a novel chemical route to functionalise biomolecules, such as antibodies and peptides. This has been developed in collaboration with AstraZeneca, and has been jointly patented (WO Application No: PCT/EP2018/070703). Antibody-drug conjugates (ADCs) are an important new therapeutic modality in the fight against cancer. ADCs can be likened to a 'magic bullet'; they use an antibody that recognises a cancer cell surface protein to specifically deliver a highly toxic payload, killing the malignant cells while limiting exposure to healthy tissue. However, there remains a number of significant issues with the core ADC components, in particular the linker portion, which if overcome would make this modality more widely applicable. Improved linker technologies would be a step forward to improve the stability of the therapeutic, reduce toxicity, and improve manufacture (no need for antibody (Ab) engineering and consistent drug dosing). We have developed a linker that in the lab can achieve all of the improvements listed above, but at this stage further testing is required within living biological systems to demonstrate its therapeutic applicability in order to secure commercialisation.
First Year Of Impact 2018
Sector Chemicals
Impact Types Economic

 
Description EPSRC IAA Follow-on Fund
Amount £60,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2020
 
Description EPSRC IAA Knowledge Transfer Fellowship
Amount £60,000 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2020
 
Description AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have been working with AstraZeneca on developing new drug discovery fragments, macrocycles and linker technologies.
Collaborator Contribution AstraZeneca have been contributing expertise, access to facilities and student funding.
Impact There will be publication outputs from this multi-disciplinary collaboration.
Start Year 2012