Professor Nick Brindle and Dr Rachel Ireland
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.
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