Postgraduate research

Directed protein evolution for predicting viral escape mechanisms and development of viral therapeutics

Qualification: PhD

Departments: Cardiovascular Sciences Molecular and Cell Biology

Application deadline: Open until filled

Start date: 26th September 2022 or 9th January 2023

Overview

Supervisors

Professor Nick Brindle and Dr Rachel Ireland

Project Description

The Department of Cardiovascular Sciences and Department of Molecular and Cell Biology are offering a fully funded 3.5 year PhD to UK applicants.

We are seeking an enthusiastic and highly motivated PhD student to study molecular mechanisms of protein:protein interactions and molecular evolution relevant to viruses. This studentship is part of a collaboration between the University of Leicester and the Defence Science and Technology Laboratory (DSTL).

Nipah virus (NiV) is a newly emerging zoonosis that causes severe encephalitic and respiratory disease in humans with a high case fatality rate of up to 92% and there are no licensed vaccines or antivirals to treat this disease (1). Furthermore, the spill-over of animal viruses such as NiV into human populations, as well as the appearance of more virulent  human viral variants, present significant current threats to health worldwide. This project will explore the use of directed protein evolution approaches (2, 3) as a platform for the accelerated development of novel NiV entry inhibitors, and to reveal potential routes of NiV evolution and virus escape from antivirals and vaccines. NiV enters host cells by binding of its surface attachment glycoprotein to host cell EphrinB2 and B3 proteins (4, 5). The student will focus on characterising the molecular interaction between the NiV surface glycoprotein and host cell receptors and will be trained in a range of advanced techniques in molecular evolution, recombinant protein expression, biochemical and biophysical characterization, protein structure determination (cryo-EM) and functional analysis, and protein:protein interactions. The study will provide proof-of-concept for application of the directed protein evolution platform to create a novel NiV antiviral, and for maximizing antiviral effectiveness by prediction of viral escape mechanisms.

References

Lawrence P., Escudero-Pérez B. Henipavirus Immune Evasion and Pathogenesis Mechanisms: Lessons Learnt from Natural Infection and Animal Models. Viruses. 2022;14(5). doi: 10.3390/v14050936.

Bate N., Lodge J., Brindle N.P. Intrinsic differences in the mechanisms of Tie2 binding to angiopoietins exploited by directed evolution to create an Ang2-selective ligand-trap. J Biol Chem. 2021;297:100888 - doi: 10.1016/j.jbc.2021.100888.

Bate N, Savva CG, Moody PCE, Brown EA, Ball JK, Schwabe JWR, Sale JE, Brindle NPJ. In vitro evolution predicts emerging CoV-2 mutations with high affinity for ACE2 and cross-species binding. 2022; PLoS Pathogens in press.

Negrete OA, Levroney EL, Aguilar HC, Bertolotti-Ciarlet A, Nazarian R, Tajyar S, Lee B. EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature. 2005;436(7049):401-5. doi: 10.1038/nature03838.

Negrete OA, Wolf MC, Aguilar HC, Enterlein S, Wang W, Muhlberger E, Su SV, Bertolotti-Ciarlet A, Flick R, Lee B. Two key residues in ephrinB3 are critical for its use as an alternative receptor for Nipah virus. PLoS Pathog. 2006;2(2):e7. doi: 10.1371/journal.ppat.0020007

Funding

Funding

Studentship funded by DSTL

Fully funded studentship for 3.5 years, stipend is £16, 062 per year increasing in line with UKRI guidance, tax free.

Funding will also cover UK tuition fees for 3.5 years. 

Entry requirements

Entry requirements

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject or overseas equivalent.  

The University of Leicester English language requirements apply

 

Informal enquiries

Informal enquiries

Project / Funding Enquiries: Prof. Nicholas Brindle npjb1@Le.ac.uk

Application enquiries to pgradmissions@le.ac.uk 

 

How to apply

How to apply

To submit your application, please use the Apply button at the bottom of the page and select September 2022 from the dropdown menu.

Include with your application:

  • CV
  • Degree Certificates and Transcripts of study already completed and if possible transcript to date of study currently being undertaken
  • Personal Statement outlining your interest in the project, your experience and why we should consider you
  • Enter contact details of two academic referees in the boxes provided or upload reference letters if already obtained
  • Evidence of English language (if applicable)
  • In the funding section specify CVS Brindle Studentship
  • In the research proposal section, include the name of the project supervisor and the project title (a research proposal is not required)

Eligibility

Eligibility

The studentship is open to UK applicants only.

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