Cryo-electron microscopes are now capturing atomic-level images of two virus families—picornaviruses and reoviruses—that together cause hundreds of millions of infections each year. These viruses are a major global health burden. Picornaviruses cause most respiratory infections and millions of hand-foot-and-mouth disease cases annually, while rotaviruses lead to several hundred million cases of severe diarrhoea. Yet no licensed drugs exist against picornaviruses, and vaccines remain scarce for both families. The fundamental problem is that scientists still lack a detailed understanding of how these viruses assemble, infect cells, and replicate—knowledge that is essential for designing new treatments. This programme uses integrated structural biology to fill those gaps. By revealing the atomic architecture of viral proteins and their interactions with host cells, the work aims to provide the molecular blueprints needed to develop novel antiviral drugs. If successful, it could accelerate the search for therapies against viruses that currently have none, potentially reducing the burden of common infections and helping to prepare for future outbreaks. This is primarily fundamental science. The immediate output will be a deeper understanding of viral mechanisms, not a finished drug. But similar structural studies of HIV and influenza have directly informed the design of existing antivirals and vaccines, making this a plausible route toward future treatments.
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Viral diseases have been responsible for massively damaging pandemics in the past, the best known example being the influenza outbreak of 1918. In recent years we have mercifully escaped such global disasters, however there is still a real and present risk. Thus the September 2019 report of the WHO Global Preparedness Monitoring Board (https://apps.who.int/gpmb/assets/annual_report/GPMB_annualreport_2019.pdf) warned that "there is a very real threat of a rapidly moving, highly lethal pandemic of a respiratory pathogen killing 50 to 80 million people and wiping out nearly 5% of the world's economy". One of their required actions is "ensure adequate investment in development of innovative vaccine and therapeutics, surge manufacturing capacity, broad-spectrum antivirals and appropriate non-pharmaceutical interventions". The programme proposed here does not primarily address lethal respiratory viruses, however it does address two important families of viral pathogens, the Picornaviridae and the Reoviridae. Picornaviruses are responsible not only for a very large proportion of respiratory tract infections, but also for other major epidemics, notably several million cases per year of hand-foot-and-mouth disease. Although one of the best known picornavirus diseases, polio, is almost eliminated there has been a concerning increase in cases recently (https://www.who.int/news-room/detail/07-01-2020-statement-o-the-twenty-third-ihr-emergency-committee-regarding-the-international-spread-of-poliovirus) and there are still serious cases of acute flaccid paralysis due to another enteroviruses. Frequent recombination events occurring between two co-infecting picornaviruses will no doubt lead to the emergence and re-emergence of numerous picornavirus caused diseases. Similarly, amongst the Reoviridae rotaviruses are estimated to cause several hundred million cases of gastroenteritis every year. Thus the viruses we propose to target represent significant global health burdens, but there are still a rather small number of vaccines available and no licenced anti-picornavirus drugs. There is a clear unmet need for novel therapeutics. Due to the continuing revolution in cryo-electron imaging it is now a golden age for structural virology and yet there remain major gaps in our understanding of how they work. The idea driving the current programme is that integrated structural biology is now sufficiently powerful that it can provide a wealth of atomic level information to feed into the search for new therapies, but can also contribute to the broader cellular level understanding of the full complexity of the virus life cycle. The goal of this programme is to make genuine contributions to answering some fundamental questions, and to at least set a direction of travel towards improved treatment.
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