Key steps in the pre-clinical development of a new drug include identifying and validating candidate targets, identifying small molecules that beneficially affect target function and biological phenotypes, characterizing the mechanisms of drug-target interaction, and using medicinal chemistry to enhance desirable therapeutic characteristics and minimize undesirable effects. Our new program integrates biological and medicinal chemistry approaches to focus on cardiovascular target discovery and drug development.
Key components that we have established are:
- Target identification using genetic approaches. We have established high-throughput cell-based screening approaches that use reporter based assays and high-content microscopy to perform phenotypic screens. We have available a variety of siRNA and lentiviral shRNA, and screening facilities at Oxford’s Target Discovery Institute. These approaches can be applied to biological questions. For instance, BMP signaling is an important pathway in cardiac fibrosis, and we have performed siRNA screens of the BMP signaling pathway using a luciferase biosensor to identify suppressors of the pathway.
- Phenotypic screens using small molecules. We have access to several commercial chemical libraries at the Target Discovery Institute, and also our in-house chemical libraries (Dr Angela Russell). These can be used for cell-based phenotypic screens using high-content microscopy. For instance we have performed small molecule phenotypic screens to identify enhancers of endothelial tube formation – using a novel high-throughput assay, that could potentially be of use in therapeutic revascularization (Dr Ayman Al-Haj Zen). We are currently developing screens for epicardial cell differentiation that could have impact on myocardial regeneration (Prof. Paul Riley).
- Target validation. We have established in vivo models where a genetically defined target identified in cells can be rapidly tested in vivo using tetracycline-inducible shRNA technology (Dr Ben Davies). This allows exquisite drug-like control of gene expression, and not only establishes if knockdown of the gene has beneficial effects but also if it has undesirable off target effects1. In addition we have established other approaches such as TALEN and CRISPR that also enable target validation.
- Novel approaches for exploring chemical space. Cyclic peptides offer a novel way of exploring chemical space (for instance a 8-mer cyclic peptide library has 208 combinations) and we have utilised cyclic peptide technologies to create and screen cyclic peptide libraries against protein targets (Dr Akane Kawamura).
- Identification of novel protein therapeutics from nature. We have developed a biotechnology platform – Bug-to-Drug – that uses yeast surface display of tick peptides. This has allowed us to efficiently mine tick salivary transcriptomes for evasin-like peptide molecules that bind chemokines. We have identified over 40 novel evasins that are potent inhibitors of chemokine signaling. They have potential application in a variety of orphan inflammatory disorders such as myocarditis and lung inflammation where the chemokine network plays a major role, and also in more common disorders such as myocardial infarction and stroke. Our goals are to pharmacologically characterize & develop these novel evasins as therapeutics, identify further evasins using the 'Bug-to-Drug' platform, use protein engineering approaches to modify properties of evasins and understand their mechanism of action using structural and mass spectrometry approaches (Prof. Shoumo Bhattacharya).
- Cardiovascular medicinal chemistry DPhil program. To train a new generation of cardiovascular medicinal chemists we have initiated a 4–year DPhil program where chemistry students are grounded in cardiovascular biology and medicinal chemistry for 2 terms, and then take on 2 rotation projects (with a chemist and a cardiovascular supervisor) after which they choose a jointly supervised DPhil project focusing on a cardiovascular medicinal chemistry / chemical biology problem. Please see the Cardiovascular Medicinal Chemistry DPhil Program site for further details.