Summary

RNA virus infections kill millions of humans annually, largely due to the lack of suitable vaccines and drugs to control them. This problem is addressed in this FP7 call and in response a consortium of Europe’s and Asia’s leading molecular virologists, structural biologists,medicinal chemists and bioinformaticians has been brought together to generate a state-of-the-art drug discovery and design programme.

WHY SILVER?

RNA virus infections kill millions of humans annually, largely due to the lack of suitable vaccines and drugs to control them. The SILVER (Small-molecule Inhibitor Leads Versus Emerging and neglected RNA viruses) project is a global consortium arising from the coordination of Europe’s and Asia’s leading molecular virologists, structural biologists, medicinal chemists and bioinformaticians. The ultimate aim of SILVER is to generate a state-of-the-art drug design programme to face new and emerging diseases caused by RNA viruses.

Aims to identify Small molecule Inhibitor Leads:

The project aims to identify Small molecule Inhibitor Leads Versus Emerging and neglected RNA viruses (SILVER). It will focus its activities on selected medically important RNA viruses for which the development of drugs is considered essential (Dengue-, entero- and paramyxoviruses), whereas other relatively neglected and/or emerging RNA viruses will be explored to identify the most promising viral protein targets and antiviral compounds.

A pipeline strategy has been developed to enable the inclusion in SILVER of viruses at all levels of existing knowledge. Targets for potential drugs include infectious virus, structurally characterised viral enzymes and other proteins. Leads for currently available antiviral drugs have been identified by screening compound libraries in virus-infected cell culture systems and in vitro assays using purified viral enzymes. Selective inhibitors of viral replication have also been (and are being) derived using detailed structural knowledge of viral proteins and structure-based drug design.

Hits will be assayed using individual viral protein targets and replicative proteins in complex with viral RNA. The potential protective activity of the most potent inhibitors, that have a favourable (in vitro) ADME-tox profile, will be assessed in relevant infection models in animals.

Licenses on promising compounds or compound classes will be presented to the interested pharmaceutical industry and will provide a multidisciplinary framework for rapid knowledge-based response to emerging infections. The SILVER consortium will be well placed to play a major role in contributing to the international effort to develop strategies to improve world health.

The research leading to these results has received funding from the European Union Seventh Programme (FP7 2007/2013) under grant agreement n°250644-SILVER