LIMR Virology: Unique Antiviral Therapy targeting Zika and Related Viruses

Summary

Zika Virus (ZIKV) has emerged as a new mosquito-borne threat to public health after the devastating South American outbreak. In addition, related viruses such as dengue virus (DENV) and tick-borne encephalitis virus (TBEV) already cause many millions of infections every year and are continuing to spread as climate change and globalization increase the range of their mosquito and tick arthropod vectors; the first cases of TBEV have now been reported in the UK.

Treating ZIKV and other “Arboviruses” (arthropod-borne) is hampered by the existence of only a small number of available vaccines (e.g. yellow fever) and a complete lack of antiviral drugs. This means that severe disease following such infections can only be combatted using supportive care, and complications such as neonatal microcephaly (ZIKV), life-threatening encephalitis (TBEV) and haemorrhagic syndromes (DENV) remain unchecked.

Drugs targeting ion channels are a tremendous success in many areas of medicine. However, whilst it is known that many human viruses encode their own essential ion channels, drugs targeting these “viroporins” are limited to prototypic medicines first licensed in the 1960s. However, we have shown that modern day drug development can be applied to viroporins, leading to the generation of potent inhibitory compounds targeting hepatitis C virus, pandemic influenza and, most recently, ZIKV.

We have discovered that the ZIKV M protein acts as a viroporin within the virion membrane, playing an essential role during virus entry. Viroporin activity was demonstrated in vitro and channels themselves are observable using electron microscopy. Moreover, drugs blocking M pevent ZIKV infection in cell culture as well as the ability of the virus to spread within mice. Molecular dynamics and medicinal chemistry has shown that we can begin to design more potent ZIKV inhibitors, which should also exert activity versus related viruses.

This project will adopt a multidisciplinary approach to deriving new small molecule inhibitors of ZIKV and its relatives with two key aims: 1) to identify candidates for future drug discovery and 2) to generate molecular tools with which to dissect the role played by viroporin activity during infection.

Techniques associated with project
Cell and virus culture including up to BSL2 and 3 biological containment, preclinical model experimentation and tissue processing/analysis, (cryo) electron microscopy and structure determination, molecular dynamics simulations, medicinal chemistry, molecular cloning, immunohistochemistry and immunofluorescence, western blotting and other proteomic analysis, virus entry and cell trafficking assays using fluorescently labelled virus particles, in vitro ion channel assays and drug inhibition, flow cytometry, recombinant protein expression and purification.

References
Scott C, Kankanala J, Foster T, Goldhill D, Simmons K, Pingen M, Bentham M, Atkins E, Loundras E, Elderfield R, Claridge J, Thompson J, Stilwell P, Tathineni R, McKimmie C, Targett-Adams P, Schnell J, Cook G, Barclay W, Foster R, Griffin S. 2019. Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza. BioRxiv (under review at PloS Pathogens)
Shaw J, Gosein R, Kalita MM, Foster T, Kankanala J, Mahato R, Scott C, King B, Brown E, Bentham M, Wetherill L, Bloy A, Samson A, Harris M, Mankouri J, Rowlands D, Macdonald A, Tarr A, Fischer W, Foster R, Griffin S. 2019. Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy. BioRxiv (under review at eLife)

This project is part of the International PhD Academy: Medical Research

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.