We have a new PhD opportunity: MRC NW-DMS DLA programme: Developing and characterising antivirals to treat neuronal complications of non-polio enterovirus infection.

 

Enteroviruses are a diverse group of picornaviruses infecting, among other sites, the central nervous system (CNS). Poliovirus, the most well known subtype causes paralysis in 1 in 200 infections and remains on the WHO eradication list. Non-polio enteroviruses are capable of causing severe infection including meningitis, myocarditis, hepatitis and acute flaccid myelitis. Two subtypes: EV-A71 and EV-D68 have emerged as strains of particular concern, listed as priority pathogens by the WHO, CEPI and UKHSA. These are widely spread viruses, with EV-D68 usually exhibiting a biannual pattern with a recent spike observed in paediatric networks and wastewater in both Europe and USA, and EV-A71 more prevalent in Asia with recent surges in Vietnam causing both hand foot and mouth and neurological complications. Currently there are no widely used vaccines or licensed antivirals for either strain.

Viral enzymes such as the 3C protease are the most effective antiviral targets, as these are viral enzymes that are not present in non-infected cells. The 3C protease cleaves a large viral protein (polyprotein) into the basic components needed for the virus to replicate. While a number of 3C inhibitors have been designed against the wider picornavirus family, none are currently in clinical use. Riputnavir, the most promising recent candidate, has failed to clear phase II trials. In addition, in clinical application, the antiviral must reach the infected compartment, as well as achieve therapeutic concentration there, including crossing the blood-brain barrier in the case of CNS infections.

Recent work on viruses with a similar 3C-like protease (coronaviruses) in the Emmott lab at Liverpool, has shown that inhibitors can target very specific phases of replication, inducing disproportionate inhibition of negative strand RNA synthesis – an essential replication intermediate for the virus. In prior MRC-funded work from the lab, they have shown conserved activity between different 3C and 3C-like proteases, including enterovirus proteases. It also builds on work within the Medicinal Chemistry group at Liverpool on 3C protease inhibitors from the pandemic, and on developing novel therapeutics with improved DMPK properties. Non-polio enteroviruses are a growing clinical problem and this includes locally, where we are collaborating with Alder Hey Childrens ‘ hospital.

In this multidisciplinary project, you will work with:

  • Emmott to gain skills in virology, proteomics, data analysis and work with our large datasets on 3C protease activity and inhibitor mode of action.
  • Michael to gain skills with their blood brain barrier model
  • Hong to gain skills in medicinal chemistry, developing antivirals with improved properties (antiviral activity, drug metabolism and pharmacokinetics (DMPK), blood-brain barrier penetration) against EV-A71/EV-D68
  • Smielewska to access current circulating clinical strains of neuropathogenic enteroviruses from Alder Hey

In this project, you will:

  1. Determine the performance of current 3C inhibitors against EV-A71 and EV-D68 in cell culture and establish blood-brain barrier models for EV-A71/EV-D68.
  2. Develop novel inhibitors based on current inhibitors and data from the supervisory team
  3. Determine mechanism of action of current and novel inhibitors

Determine performance against current circulating enterovirus strains.

Supervisory Team:

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in Biochemistry or Medicinal Chemistry. Any prior research experience in cell culture, virology, or LC-MS/MS or with microfluidics is desirable.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our English Language requirements page to find out more.

 

For more details, including how to apply – please see the FindAPhD page.

 

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