Development of new serine protease inhibitors by optimisation of rationally designed covalent S1 fragments

Serine proteases are enzymes that cleave peptide bonds in proteins, where the serine serves as the nucleophilic amino acid within the active site. The discovery of new oral drugs to inhibit serine proteases has proven problematic with the requirement to balance basic and highly ionised functional groups, required for biological activity with oral absorption (Drag Nat.Rev.DD 2010).
Guided by X-Ray structural work, the project will investigate the design and organic synthesis of novel non-basic compounds that interact with amino acids within the protease S1 binding pocket to generate highly ligand-efficient molecules for fragment-based optimisation (Ghosh 2015). Functional groups will be chosen to extend from the fragments into the catalytic oxyanion hole to give series of slow off-rate/covalent inhibitors through the synthesis of rationally-designed chemical warheads (Traube Eur.JMC 2014). In the initial arm of the project, inhibitors of plasma kallikrein will be synthesised as it has been shown that excessive activity of the plasma kallikrein system contributes to hereditary angioedema and is also strongly implicated in diabetic macular edema, cerebral hemorrhage, and other inflammatory disorders (Teufel JMC 2018). In a second phase of the project, principles discovered will be applied to other therapeutically-important and structurally-related trypsin-like protease targets in the thrombosis, inflammation, anti-microbial and cancer areas.
The multi-disciplinary project will have a strong synthetic chemistry focus, with the student gaining training on key experimental techniques and equipment employed in modern synthetic organic/medicinal chemistry. The critical exploitation of reagents for the successful completion of multi-step synthetic strategies followed by product isolation/purification and the unambiguous identification of all new products will ensure the student becomes proficient in the running and interpretation of modern chemistry methods. Computational chemistry will be used to guide the design of the target molecules and predict new interaction sites for ligands bound into the serine protease active site.
The generated compounds will require full pharmacological characterization (performed in-kind at KalVista), therefore the multidisciplinary nature of this project will provide the student insight into several areas of medicinal chemistry, key skills required to launch their own academic or pharmaceutical industry career.