Research in the Lovell Lab
The overall goal of our research is to develop new chemical modalities that can be used to selectively engage difficult-to-drug protein targets inside or outside diseased cells. Ultimately, we aim to use molecules generated in our lab as starting points for the development of new drugs to treat patients with cancer or antibiotic-resistant infections. We are proud to be part of the Department Life Sciences at the University of Bath and to be a member of the Institute for Sustainability and Climate Change.
Up to 85% of human proteins are deemed 'undruggable' as they function through protein-protein interactions (PPI), which are difficult to disrupt with small molecules. Many of these proteins play important roles in cancer progression.
We use targeted covalent macrocycles (TCMs) to inhibit intracellular undruggable cancer proteins. TCMs combine the properties of a macrocyclic peptide and a covalent inhibitor, binding to shallow PPI interfaces with high affinity and selectivity by forming interactions over a large surface area and achieving permanent target engagement by covalent modification of a proximate nucleophilic residue.
Using innovative resin-based chemistries, state-of-the-art robotics and mass spectrometry, we generate large libraries of TCMs for screening against protein targets.
Targeted Covalent Macrocycles
Macrocyclic peptide conjugates
We generate billions of macrocycles by cyclising linear peptides displayed on phage particles with novel chemical linchpins.
Billion-member libraries are screened against membrane-bound or extracellular proteins secreted by cancer cells or pathogenic bacteria to identify hit macrocycles.
Hit macrocycles are conjugated to fluorescent or cytotoxic payloads to enable selective destruction or imaging of diseased cells and tissues.
We combine synthetic chemistry, molecular biology and chemical biology techniques to enable rapid peptide drug discovery.
Activity-based Probes
Proteolysis is frequently dysregulated in cancer and contributes to disease severity and progression. We use activity-based probes (ABPs) to inhibit, quantify and image the activity of individual proteases in different cancers.
ABPs possess an electrophilic warhead that modifies the hyper-reactive catalytic residue of proteases. A specificity element guides the ABP scaffold to the protease of interest. A tag enables quantification of proteolytic activity by fluorescence imaging or mass spectrometry.
We are particularly interested in a family of proteases called Kallikreins and are developing next-generation ABPs to enable selectively delivery of cytotoxic payloads to Kallikrein-expressing cancer cells.
Funding
We are thankful to the following organisations for their ongoing support:
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University of Bath
AdvanCell Isotopes Ltd
The Academy of Medical Sciences
The Royal Society
EPSRC
AdvanCell Isotopes Ltd