RNA viruses include more than 350 different major human pathogens and most of the etiological agents of emerging or re-emerging diseases: gastroenteritis (>1 million deaths annually), measles (>45 million cases and >1 million deaths annually), influenza (>100 million cases annually), dengue fever (300 million cases annually), enteroviruses and encephalitis (several million cases of meningitis annually), hepatitis C virus (>150 million infected people worldwide).
The devastating economic impact of an epidemic caused by an emerging virus was demonstrated during the SARS outbreak in 2003-2004. And with the threat of bio-terrorism, which lists some deadly RNA viruses in its arsenal, many governments are forced to take costly protective measures.
To meet these challenges scientists need to look for new therapeutic and prophylactic treatments active against RNA viruses, since those currently available are scarce and of poor potency. The common strategies used for the development of antiviral drugs are mainly based on the knowledge accumulated through studies of virus genetics and structure. However, it is a strange paradox that genomic and structural characterization of RNA viruses has not been accepted as a priority until very recently.
To address these urgent needs, VIZIER has brought together leading European authorities on RNA viruses, structural biology and structural genomics as well as participants fully equipped with high level bio security P4 laboratories. A concerted program of structure determination is required and now feasible, as demonstrated by the development of protocols for high-throughput (HTP) protein production, facilitated by National and European projects such as the pilot Integrated Project SPINE.
The VIZIER consortium will study RNA-based viruses, i.e viruses that do not include a DNA stage in their replicative cycle. These form three genetically different classes, namely double-stranded and single stranded RNA viruses with positive and negative polarity, dsRNA, ssRNA+ and ssRNA-, respectively. These classes employ profoundly different replicative mechanisms driven by poorly characterized replication machineries. Although virus-specific, they are the most conserved and essential viral components and, thus, the most attractive targets for antiviral therapy. The VIZIER consortium will therefore characterize the core enzymes/proteins of the replication machinery, among 300 carefully selected different RNA viruses, including strains of medical interest. These proteins include polymerases, helicases, capping enzymes, NTPases, and proteases as well as ancillary replicative proteins. Comparison of their sequence, structure and function is furthermore expected to drastically advance our understanding of the fundamentals of replication mechanisms for most RNA virus lineages.
A unique feature of VIZIER, compared to similar projects, is the integration of major structural efforts within a broad multidisciplinary pipeline study, with virology upstream and target validation (lead design) downstream. As a result, the implementation plan is structured into 5 interacting scientific sections: (i) bioinformatics, for genome annotation, target selection and data integration; (ii) virus production and genome sequencing; (iii) HTP protein production (1200-1800 targets); (iv) HTP crystallization and structural determination and (v) target validation, to assess the function of enzymes and design strategies for virus inhibition.
Novel tools for protein production along with multi-sites and networked X-ray crystallography will be developed and validated. The latter will enable fast dissemination of the acquired knowledge and expertise within the European Union, inside and outside the project, including countries not previously involved in structural genomics projects.
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