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Assistant Professor Lok is one of the recipients for the prestigious National Research Foundation fellowship. Dengue Virus (DENV) infects approximately 100 million people each year. Increased travel, together with global climate change will result in further geographical expansion of the territory of the dengue mosquito vector, Aedes aegypti. There is an urgent need to develop safe and effective dengue therapeutics and vaccine.
In vitro experiments have shown that non-neutralizing antibodies can enhance DENV infection of Fc receptor bearing macrophages, one of the natural host cells for the virus. This suggested that the presence of non-neutralizing epitopes in a vaccine could potentially increase the chances that a person who had received the vaccine would develop the severe form of the disease, dengue hemorrhagic fever. For this reason, a more promising approach for engineering an effective DENV vaccine is to focus on including neutralizing epitopes. Thus, mapping of neutralizing epitopes is a necessary component of DENV vaccine research. Furthermore, understanding the neutralization mechanism of antibodies and the entry of DENV into the host cells also could aid in the design of targeted therapeutics.
The research in her laboratory therefore, focuses on the understanding of the pathology of dengue virus infection and the mechanism of neutralization by antibodies and other molecules so as to facilitate the development of suitable vaccines and therapeutics. A combination of molecular, immunological, biochemical and structural techniques (x ray crystallography and cryoEM image reconstruction techniques) will be used to achieve these aims.
Lok, S.-M. (2014). Human antibodies stop dengue virus by jamming its mechanics. Proceedings of National Academy of Sciences USA. 111:1670-1671.
Kostyuchenko, V.A., Chew, P.L., Ng, T.-S. and Lok, S.-M. (2014). Near-atomic resolution cryo-EM structure of Dengue serotype 4 virus. Journal of Virology. Vol 88: 477-482. (Selected for cover page)
Fibriansah, G., L. Tan, J.L., de Alwis, R., Smith, S.A., Ng, T.-S., Kostyuchenko, V.A., Ibarra, K.D., Harris, E., de Silva, A., Crowe, J.E., Jr. and Lok, S.-M. (2014). A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Molecular Medicine. In press. (Selected for cover page)
Fibriansah, G., Ng, T.-S., Kostyuchenko, V.A., Lee, J., Lee, S., Wang, J. and Lok S.-M. (2013). Structural Changes in Dengue Virus When Exposed to a Temperature of 37oC. Journal of Virology, Vol 87:7585-92. (Selected for cover page and article featured in a Nature commentary article)
Kostyuchenko, V. A., Zhang, Q., Tan, J.L., Ng, T.-S. and Lok, S.M. (2013). Immature and mature Dengue serotype 1 virus structures provide insight into the maturation process. Journal of Virology. Vol 87:7700-7.
Veesler, D., Ng, T.-S., Sendamarai, A.K., Eilers, B.J., Lawrence, C.M., Lok, S.-M., Young, Johnson, J.E. and Fu, C.-Y. (2013). Life in the extremes, atomic structure of sulfolobus turreted icosahedral virus. PNAS. Vol 110:5504-5509.
Zhang, Q., Hunke, C., Yin-Hoe Yau, Y.-H., Seow, V., Lee, S., Tanner, L.B., Guan, X.L., Wenk, M.R., Fibriansah, G., Chew, P.L.,Kukkaro, P., Biuković, G., Shi, P.-Y., Shochat, S.G., Grüber, G. and Lok, S.-M. (2012). The stem region of premembrane protein plays an important role in the virus surface protein rearrangement during dengue maturation. Journal of Biological Chemistry. Vol 287:40525-40534.
Teoh, E.P., Kukkaro, P., Teo, E.W., Lim, A.P., Tan, T.T., Yip, A., Schul, W., Aung, M., Kostyuchenko, V.A., Leo, Y.S., Chan, S.H., Smith, K.G., Chan, A.H., Zou, G., Ooi, E.E., Kemeny, D.M., Tan, G.K., Ng, J.K., Ng, M.L., Alonso, S., Fisher, D., Shi, P.Y., Hanson, B.J., Lok, S.-M.* and MacAry, P.A.* (2012). The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Natural Human Antibody. Science Translational Medicine. Vol 4:139 * co-corresponding authors
Dong, H., Chang, D.C., Hua, M.H., Lim, S.P., Chionh, Y.H., Hia, F., Lee, Y.H., Kukkaro, P., Lok, S.-M., Dedon, P.C. and Shi, P.Y. (2012). 2’-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase. PLOS Pathogen.Vol 8(4).
Kostyuchenko, V.A., Jakana, J., Liu, X., Haddow, A.D., Aung, M., Weaver, S.C., Chiu W, Chiu, W.*, and Lok, S.-M.*(2011). The 6Å resolution cryo-EM Barmah Forest virus structure shows detailed transmembrane proteins architecture and interactions. J Virol. 2011 Sep;85(18):9327-33.
Cherrier, M.V., Kaufmann, B., Nybakken, G.E., Lok, S.-M., Warren, J.T., Chen, B.R., Nelson, C.A., Kostyuchenko, V.A., Holdaway, H.A., Chipman, P.R., Kuhn, R.J., Diamond, M.S., Rossmann, M.G. and Fremont, D.H. (2009). Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J. 28: 3269-3272.
Li, L., Lok, S.-M., Yu, I.M., Zhang, Y., Kuhn, R.J., Chen, J. and Rossmann, M.G. (2008). Structure of the flavivirus precursor membrane-envelope protein complex and its implication for maturation. Science. 319: 1830-1834.
Lok, S.-M., Kostyuchenko, V., Nybakken, G.E., Holdaway, H.A., Battisti, A.J., Sukupolvi-Petty, S., Sedlak, D., Fremont, D.H., Chipman, P.R., Roehrig, J.T., Diamond, M.S., Kuhn, R.J. and Rossmann, M.G. (2008). Binding of a neutralizing antibody to dengue virus resulted in an altered arrangement of the surface glycoproteins. Nature Structural and Molecular Biology. 15 (3): 312-317.
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