The global burden of dengue has grown dramatically in recent decades, and it is currently classified as a re-emerging infectious disease. Dengue fever (DF) and dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS) occur in over 100 countries, with more than 2.5 billion people at risk and an estimated 50 million infections per year. The major disease burden is found in south-east Asia and the western Pacific, with increased reporting of DF/DHF in the Americas. There is currently no treatment for dengue diseases per se, only supportive care. DHF/DSS is a leading cause of hospital admissions and death amongst children in most Asian countries. The strain put on countries' healthcare systems during a dengue epidemic can be quite staggering, both financially and with respect to resources, especially in developing countries. Dengue epidemics are often well publicized in the press and have the attention of governments and ministries of health because of the burden on the health resources and the economy.
The increasing number of dengue epidemics in the endemic countries within the tropical/sub-tropical regions of the world may be due to new virulent strains or higher rate of secondary dengue infections. Both situations can lead to increased viremia and this has been directly correlated with severe dengue diseases (DHF and DSS). By comparison patients suffering from classical dengue fever appear to have a lower viral load (Libraty et al., Journal of Infectious Diseases, 2002, 185:1213-21). Leading from this observation, our strategy is to find medicines that reduce the viral load so that morbidity and mortality associated with dengue will be lowered and this will then lead to a lower rate of transmission of the virus. We will:
- Identify small molecules that can interfere with viral replication either by blocking essential virus/host membrane fusion, preventing polyprotein processing or inhibiting RNA replication i.e. to find dengue virus inhibitors that bind directly to viral targets such as the NS3 protease, helicase or polymerase or their macromolecular complexes
- Test dengue inhibitors for their action on homologous targets in other important human-disease-causing-flaviviruses such as West Nile Virus, Japanese Encephalitis Virus, Yellow Fever Virus or Tick Borne Encephalitis Virus in a platform approach to identify pan-flavivirus inhibitors
- Discover and validate non-immune host targets that permit viral replication or are directly required for replication and assess their druggability through extensive use of new technologies available both within Novartis (Functional Genomics Area) and other partner institutions (e.g. Genome Institute of Singapore).
The Dengue Unit is staffed with nearly 24 scientists to achieve the above goals together with the scientist from Chemistry and Pharmacology Units. Specifically the dengue unit scientists will carry out in vitro assays using cloned enzymes/proteins, cell-based assays with infectious virus and/or replicons (non-infectious), animal model for viremia, structural studies of targets, biomarker identification and also contribute together with an international network of partners (including members of the Singapore Dengue Consortium), towards a better understanding of dengue pathogenesis in patients through carefully planned prospective studies.
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Novartis Institute for Biomedical Research
