SILVER

EC contribution

: € 12.000.000

Duration

: 48 months

Starting date

: 01/10/2010

Funding scheme

: Collaborative project - Large scale

Keywords

: RNA viruses, replicative enzymes, viral inhibitors, antiviral therapy, viral therapeutics, emerging viruses, neglected viruses, structure-based drug design

Contract/Grant agreement number

: 260644

Project web-site

: In preparation

Problem:

Increasing human and animal population density through urbanisation and agricultural climate change, all have an impact on virus emergence and epidemiology. Over the past 3 decades, emerging RNA viruses continuously gripped the world's attention, either briefly (SARS coronavirus), or continuously (human immunodeficiency virus [HIV],avian and swine influenza viruses and hepatitis C virus [HCV]). Many other RNA virus threats were identified or "re-discovered", including a variety of pathogenic flaviviruses (dengue virus [DENV] and West Nile virus[WNV]), filoviruses (Ebola and Marburg viruses), emerging picornaviruses (enterovirus 71), known and emerging paramyxoviruses (respiratory syncytial virus [RSV], human metapneumovirus [hMPV], Nipah and Hendra virus), alphaviruses (chikungunya virus), novel human coronaviruses, noroviruses, arenaviruses (Lassa fever virus) and hantaviruses (including hantavirus with pulmonary syndrome). Expert opinion predicts that novel and potentially highly pathogenic agents will continue to emerge from the large, genetically variable natural virus pools surrounding us. We urgently need advanced levels of preparedness with which to confront and ultimately control these viral pathogens. As illustrated by the success of anti-HIV therapy (mainly in the Western world) and recent events involving the novel H1N1 influenza virus, the ability to inhibit virus replication using prophylactic or therapeutic strategies could be a major cornerstone in our battle against emerging and relatively neglected viruses. Today, antiviral drugs are only available for the treatment of infections with (i) HIV, (ii) some DNA viruses (herpesviruses, hepatitis B virus, poxviruses) and (iii) a small number of RNA viruses [HCV (the first selective inhibitors are expected to be approved in 2011, i.e. 22 years after the discovery of the virus), RSV, and influenza virus]. Decades of rigorous effort were needed to develop these drugs and specific therapy is still lacking for the treatment of infections by all other RNA viruses, leaving supportive care as the only option.

The structural and non-structural viral proteins that orchestrate the steps in the viral replicative cycle are potentially vulnerable targets for "attack" by appropriate ligands that interfere with their functionality. The virus-specific nature of these targets and functions provides the potential to limit the negative side effects of antiviral drug treatment on regular host cell processes. Leads for the majority of currently available antiviral drugs were identified by screening compound libraries in cell culture-based systems (either employing infected cells or minigenome/replicon systems) and in vitro assays using purified viral enzymes. Increasingly, however, selective inhibitors of viral replication are derived from structure-based drug design [SBDD] and detailed structural knowledge of viral proteins. The major part of the momentum for the current SILVER project was generated by the FP6 VIZIER platform for HTP viral genomics and structural biology (FP6-511960; http://www.vizier-europe.org/), smaller virus-specific FP6 projects, and the FP7 European virus archive (EVA FP7-228292; http://www.european-virus-archive.com), to which a substantial number of partners of the present consortium contributed. Most of the resources generated during the course of these projects are in the public domain, and are therefore readily available for SILVER partners.

Aim:

The overriding aim of SILVER will be the discovery and development of novel strategies to inhibit viral replication, and ultimately the selective inhibition of RNA viruses.

(Expected) results:

1. Potential viral inhibitors for integration into the SILVER pipeline,
2. crystal structures in complex with RNA and other ligands deposited in the Public Database,
3. lead inhibitory compounds against selected viruses,
4. demonstrable efficacy of newly identified inhibitory compounds in relevant models (proof of concept),
5. exploitation of inhibitors through SMEs and larger Pharma,
6. Development of IP through SILVER's global network of contacts in academia, industry and government.

Potential applications:

Therapeutics for treatment of human and/or animal virus disease.

Coordinator:

Co-coordinator:

Partners: