Use of Affimer Affinity Reagents to Detect Changes in Protein Structure
Medical Research Scotland
PhD Studentship Award
This project is one of 15 PhD Studentships funded by Medical Research Scotland (http://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and Company. The Studentship will provide the first-class academic and commercial training needed to equip the successful candidate for a science career in an increasingly competitive market.
"Use of Affimer Technology to discriminate between Agonist- and Antagonist-induced Conformational Changes in the Cyclic-nucleotide Binding Domain (CNBD) Protein, EPAC1" to be delivered by the Heriot-Watt University [Supervisors: Dr Stephen Yarwood (School of Life Sciences, Heriot-Watt University), Professor Dave Adams (School of Engineering & Physical Sciences, Heriot-Watt University) and Dr Brian Smith, Institute of Molecular, Cell and Systems Biology, University of Glasgow)] and Avacta Life Sciences Ltd (www.avactalifesciences.com) [Company supervisor: Professor Paul Ko Ferrigno].
There is an urgent need to develop new therapeutic strategies to combat the “chronic inflammation” associated with cardiovascular diseases (CVDs), which are the cause of some 187,000 premature deaths in the UK per year. Chronic inflammation can develop due to increased levels of inflammatory “messengers”, or cytokines, in the circulation. In the case of conditions like atherosclerosis, this inflammation involves excessive “leakiness” and increased attachment of white blood cells to the vascular endothelial cells (VECs) that line the blood vessels. This causes long term damage, including blocked arteries and blood clots, which can lead to heart attacks or strokes. Moreover, attempts to use “stents” to restore blocked arteries often fail due to localised inflammatory activity.
We have discovered that activation of the enzyme, EPAC1, can suppress this inflammatory activity. We will, therefore, generate "artificial antibodies", or "Affimers", which will allow us to develop new activators of EPAC1 with the potential to suppress damaging inflammation in VECs. Affimers are engineered proteins that bind to bio-molecules in ways similar to antibodies, but can be expressed in cells without loss of activity and have been used as co-crystallisation chaperones and for structure-based small molecule screening. With Avacta Life Sciences, the student will carry out phage-display screens to identify Affimers that can discriminate between the different conformational states of EPAC1 (ie un-bound, agonist-bound or antagonist bound). Affimers will then be expressed in VECs to assess their effects on EPAC1 function and will form the basis of new drug screens to identify novel small molecule EPAC1 regulators that can be used to combat CVDs.
Enquiries should be sent by email to Dr Stephen Yarwood:
[Email Address Removed]
Candidates must have obtained, or expect to obtain, a first or 2.1 UK BSc Honours degree, or equivalent for degrees obtained outside the UK, in chemistry or a relevant biological science (eg biochemistry, biotechnology, pharmacology etc).
Applicants should send an up-to-date CV; letters of reference from two academic referees; and a covering letter, explaining why the applicant wishes to carry out this project, by email to Dr Stephen Yarwood:
[Email Address Removed]
Interviews are expected to take place 3-4 weeks after the closing date for applications.
It is anticipated that the PhD Studentship will start in October 2016.
PhD Studentship provides: an annual tax-free stipend of £17,500, increasing to £18,000 over the four years; tuition fees at UK/EU rates only; consumables; and contribution to travel expenses. International fees are not covered.