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


Project Description

The PhD studentship is an EPSRC Doctoral Training Partnership (https://epsrc.ukri.org/skills/students/dta/termsconds/) in collaboration with KalVista Pharmaceuticals a pharmaceutical company focused on the discovery, development, and commercialisation of small molecule protease inhibitors for diseases with significant unmet medical need.
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. 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. Functional groups will be selected 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. In the initial arm of the project, inhibitors of plasma kallikrein will be synthesised as excessive activity of the plasma kallikrein system contributes to hereditary angioedema. There is strong evidence that this effect contributes to diabetic macular oedema, cerebral haemorrhage, and other inflammatory disorders. Eventually, principles discovered within the project, will be applied to other therapeutically important and structurally related trypsin-like protease targets in the thrombosis, inflammation, anti-microbial and cancer areas
The project will have a strong synthetic chemistry focus, with the student gaining specific training on the use of key experimental techniques and equipment employed in modern synthetic organic medicinal chemistry.
Training in synthetic medicinal chemistry will give the research student a strong platform to launch their future career.
The work, based in the School of Pharmacy in Nottingham will include a 6-month industrial placement at KalVista pharmaceuticals.
Informal enquiries to: Dr Michael Stocks () and Professor Jonas Emsley ()

Funding Notes

The project is available from 1st October 2019 and will be of 4-year duration. The studentship is open to UK and EU students with a minimum of a 2(i) degree in chemistry, pharmacy or a related discipline. This award includes University tuition fees for a student with EU/UK citizenship, and a stipend at standard EPSRC rates. Due to funding restrictions, this studentship is only open to UK/EU students. EU students are only eligible to receive tuition fees (no stipend), unless they fulfil residency criteria. More details about eligibility criteria are available at: View Website

How good is research at University of Nottingham in Allied Health Professions, Dentistry, Nursing and Pharmacy?
Pharmacy

FTE Category A staff submitted: 44.10

Research output data provided by the Research Excellence Framework (REF)

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