We are seeking an enthusiastic and motivated PhD candidate to study how the Dengue virus enzymes NS3 and NS5 assemble for viral replication and develop high-throughput assays for small molecule screening.
Dengue virus infects ~390 million people and kills ~20,00 people, including children, annually, mostly in tropical climates. Few drugs are licensed for RNA viruses in general and none for Dengue or other flaviviruses.
A structure-guided approach accelerates drug discovery but requires information about the structure and organization of protein targets. The Dengue virus replication complex is an assembly of 7 non-structural proteins that replicates the short RNA genome of the virus. Equivalent complexes are targeted in other anti-viral treatments, such as against Hepatitis C (a close relative of Dengue), HIV, SARS-CoV-2 and the Herpes Simplex type 1 virus. However, the assembly of the Dengue virus replication complex remains poorly characterised.
Here, you will use structural biology and biophysics methods to determine how the two Dengue enzymes, NS3 and NS5, interact at the heart of this complex. You will collect electron microscopy and small angle X-ray scattering (SAXS) data and build a model of the NS3-NS5 complex using previous X-ray structures of the individual proteins. Subsequently, you will develop high-throughput assays to screen small molecules that inhibit the assembly and enzyme activities of this complex. This will enable future in vitro and in silico drug discovery efforts.
You will gain training in the following techniques:
- Single particle electron microscopy
- SAXS
- X-ray crystallography
- Protein structure prediction, such as AlphaFold
- Developing high-throughput enzymological assays to screen small molecules
- Förster resonance energy transfer (FRET) assay development
- Recombinant protein expression and purification
About You:
You must possess or expect to obtain a first or upper second class Master’s or a first class Bachelor’s degree with relevant experience in Biochemistry, Biology, Chemistry or a related discipline. This project will suit someone with a keen interest in the structures of proteins and a curiosity in structure-guided drug discovery. Prior experience in structural biology, biophysics or enzymology is not required.
About Us:
This project is hosted by Dr Liz Morris, Assistant Professor (Biochemistry) within the Durham University Biosciences Department. Here, you will join a team of Bioscientists working alongside Chemists studying biomolecular interactions. We have state-of-the-art facilities for protein production, protein biophysics, enzymological assay development and X-ray crystallography. In addition, you will get training in electron microscopy in Dr Jon Marles-Wright’s lab, Senior Lecturer in Newcastle University’s School of Biology.
Durham University, where you will primarily be based, is an outstanding centre of research and teaching excellence. Here you will join one of the University’s seventeen colleges through which you can access student-led activities, such as sports, theatre, music or volunteering, as well as welfare support.
How to Apply
Please refer to the following webpage for information on how to apply for this project: Durham | MoSMed CDT | Newcastle University (ncl.ac.uk)
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