Small-molecule Inhibitor Leads Versus Emerging and neglected RNA viruses
The project will focus its activities on selected medically important RNA viruses for which the development of drugs is considered essential ("Group A: priority viruses"); other relatively neglected and/or emerging RNA viruses will be explored through careful selection of the most promising targets and antiviral compounds. New antiviral hit compounds will be discovered by state-of-the-art cell culture-based screening, by screening in enzymatic assays for specific viral proteins, and by structure-based drug discovery. The hits identified by these methods will be optimized by medicinal chemistry, guided by the structure of the viral target where available. For the most promising antiviral lead compounds, proof-of-concept will be sought in small animal studies. A pipeline strategy will be employed to progress this work plan, as illustrated in Fig. I
Fig 1: The SILVER Drug Development Pipeline, with colour codes referring to the tasks of Work Packages 1-4 (WP1, blue; WP2, red, WP3, green; WP4, yellow).
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.
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.
Therapeutics for treatment of human and/or animal virus disease.