Novartis Institute for Tropical Diseases (NITD)
Fighting neglected infectious diseases
The Novartis Institute for Tropical Diseases (NITD), one of the institutes of the Novartis Institutes for BioMedical Research (NIBR), is dedicated to finding new medicines to treat neglected, infectious diseases. As a small-molecule drug discovery research institute, it combines the drug-discovery expertise and cutting-edge technologies of Novartis to fight infectious tropical diseases, including Dengue fever, Human African Trypanomiasis and Malaria among others.
In developing countries where these diseases are endemic, Novartis will make treatments accessible to the communities that need them. NITD was set up as a public-private partnership between Novartis and the Singapore Economic Development Board (EDB) in 2002. Since then, it has grown to more than 100 researchers and supporting staff. As a major center of excellence for drug discovery, NITD will offer exceptional teaching and training opportunities for post-doctoral fellows and graduate students.
Training scientists from developing world in drug discovery
One of the challenges of discovering drug for diseases of the developing world is the lack of basic research into the underlying causes of these diseases – an example of this is dengue fever. Dengue fever is caused by any one of -the four serotypes of dengue viruses transmitted by mosquitoes. The challenge in dengue drug discovery is the limited knowledge about virus infection cycle and the lack of understanding of the relationship between viremia and severe disease progression. Novartis is one of the few large pharmaceutical companies working on research for dengue fever at NITD.
About 2.5 billion people, or 40 percent of the world’s population, lives in areas where there is a risk of dengue transmission and a certain small percentage of the infected patients develop into -life-threatening hemorrhagic fever and shock syndrome that can lead to death. Over the past four decades, dengue disease has become recognized as the world's most important mosquito-borne viral disease.
The NITD dengue team has worked with many of Singapore local and international collaborators to establish novel research tools and approaches, characterizing NS4B target to enable -drug discovery, establishing -Dengue animal models for antiviral testing, defining structure and function of Dengue viral proteins, and developing screening assays which have been used to identify several candidate compounds in the fight against dengue.
- Dong, H., Chang, D.C., Hua, M.H.C., Lim, S.P., Chionh, Y.H., Hia, F., Lee, Y.H, Kukkaro, P., Lok, S.-M., Dedon, P.C., and Shi, P.-Y. 2012. 2O methylation of internal adenosine by flavivirus NS5 methyltransferase. PLoS Pathogens. 8(4), e1002642.
- Xie, X., Gayen, S., Kang, C., Yuan, Z., and Shi, P.-Y. 2013. Membrane topology and function of dengue virus NS2A protein. J. Virol. 87(8):4609-22.
- Noble, C.G., Lim, S.P., Chen, Y.-L., Larbi, D., Liew, C.W., Yap, L., Lescar, J., and Shi, P.-Y. 2013. Conformational flexibility of the dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor. J. Virol. 87(9):5291-5
Medicinal Chemistry – making new and better drugs through chemistry
Drugs developed for developing world diseases need to meet additional challenges aside from efficacy and safety such as stability under tropical conditions and low cost of goods to enable access for patients living in poverty. In endemic areas people often travel long distances to get to clinics and require medicines that can work quickly with only a few inexpensive doses and don’t require follow-up visits. NITD has focused on developing small molecule based medicines that can meet these requirements by leveraging their expertise in medicinal chemistry with the goal of designing of molecules with the best possible safety and efficacy. Medicinal chemistry combines organic chemistry, pharmacology, and other specialized fields for the design, synthesis, and development of new drugs.
In South East Asia, the first signs of drug resistance against the malaria parasite have been reported and new drugs different from the current arsenal of antimalarials are needed to fight the resistant parasites. NITD has developed and is currently testing two potential treatments in patient trials, including a promising new candidate against drug-resistant malaria which is active on both vivax and falciparum malaria. This new class of antimalarial compound, termed spiroindolones, was discovered and developed from a chemical hit out of the Novartis Compound Library. An extensive medicinal chemical optimization campaign which focused on improving the activity and the physicochemical or drug-like properties of the molecule lead to the development of KAE609. KAE609 is the first new class of antimalarial with a different mode of action to the current drugs to enter clinial trials in over 20 years.
- Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P. J., Lindegardh, N., Socheat, D., White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 36, 455-467.
- Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., Gonz, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H.-P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T. H., Fidock, D. A., Winzeler, E. A., and Diagana, T.T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175-1180.
- Meister, S., Plouffe, D. M., Kuhen, K. L., Bonamy, G. M. C., Wu, T., Barnes, S. W., Bopp, S. E., Borboa, R., Bright, A. T., Che, J., Cohen, S., Dharia, N. V., Gagaring, K., Gettayacamin, M., Gordon, P., Groessl, T., Kato, N., Lee, M.C.S., McNamara, C. W., Fidock, D.A., Nagle, A., Nam, T. G., Richmond, W., Roland, J., Rottmann, M., Zhou, B., Froissard, P., Glynne, R. J., Mazier, D., Sattabongkot, J., Schultz, P.G., Tuntland, T., Walker, J. R., Zhou, Y., Chatterjee, A., Diagana, T. T., Winzeler, E. A.(2011). Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372-1377.
Screening drugs – finding drugs that are effective against neglected diseases
Screening for drugs effective in infectious diseases is challenging because of the often limited understanding of the pathophysiology of the disease. The best way to screen is thus to use the whole organism and look for compounds that cause cell death – Human African trypanosomiasis is one example. An estimated 70 million people, in sub-Saharan Africa are at risk of contracting Human African trypanosomiasis or sleeping sickness, a parasitic disease caused by the protozoan Trypanosoma brucei, which is transmitted by the bite of the tsetse fly. 7197 new cases were reported in 2012, however it is acknowledged that cases are under-reported and that WHO estimates the number of actual cases to be 30000 (Ref. World Health Organization Factsheet No.259: http://www.who.int/mediacentre/factsheets/fs259/en/index.html). Current treatments have complicated administration regimes and have serious adverse side-effects.
NITD has a state-of-the-art screening laboratory equipped with a GNF automated screening platform that can screen compound libraries against both target and cell-based assays including the pathogens (Dengue virus, Plasmodium falciparum and Trypanosoma brucei species). GNF tested the entire Novartis compound collection for anti-trypanosomal activity, and a large number of actives (hits) were identified in the screen. Initial inspection of the hits indicates that many are novel compounds and have good lead-like properties making them highly suitable for further evaluation at NITD.