Viruses continue to pose a significant threat to public health worldwide. Treatment options predominately include vaccines, and antiviral drugs. Vaccines, however, are not readily available for many viruses, and antiviral agents often give rise to drug resistance. Furthermore, viruses may have more than one serotype or strain, and this complicates the development of treatment options.
To design better therapeutics and vaccines, the highly complex viral infection process must be better understood, from pathogenesis and replication through to transmission.
Taking a structural biology approach to this challenge is Professor Lok Shee-Mei, who specialises in X-ray crystallography and cryo-electron microscopy. Her laboratory studies the interactions and structural changes of viruses during the infection process and explores how therapeutics such as antibodies could inhibit various stages of the process. Of particular interest to Prof Lok are the morphologies of flaviviruses (dengue and Zika viruses) and alphaviruses (Sindbis and chikungunya viruses). Defining their structures may facilitate the development of nextgeneration vaccine and interventions.
Prof Lok discovered that the dengue virus changes shape at different temperatures. For instance, the dengue virus is typically in a compact ball-arrangement at 28°C. When it enters the human host of 37°C, it puffs up to reveal new surfaces in response to the increased temperature. This change in shape hinders vaccine development as the different structures must be introduced into the vaccines for the human body to recognise all of them. However, the shape change of the dengue virus also exposes weak spots on the surface of the virus that were previously hidden, allowing the design of therapies and vaccines to target these exposed surfaces and treat dengue.
Prof Lok also imaged the highresolution structure of the poorly understood Zika virus, revealing that the virus is more thermally stable than other flaviviruses. By understanding the structure of the Zika virus, therapeutics such as antibodies and vaccines can be developed to destabilise the structure of the virus, ultimately reducing infection rates.
Prof Lok is a recipient of the prestigious National Research Foundation (NRF) Fellowship (2009) and NRF Investigatorship (2016).
Targeting important epitopes with antibodies to quicken the development of treatment strategies and accelerate vaccine development
Understanding structural changes in viruses such as dengue and Zika
Discovery of such vulnerabilities offers exciting possibilities for the development of drugs to target these weak spots for treatment of dengue and related viruses such as Zika
Fibriansah, G., Lim, E. X., Marzinek, J. K., Ng, T. S., Tan, J. L., Huber, R. G., ... & Lok, S. M. (2021). Antibody affinity versus dengue morphology influences neutralization. PLoS pathogens, 17 (2), e1009331.
Zhou, Q. F., Fox, J. M., Earnest, J. T., Ng, T. S., Kim, A. S., Fibriansah, G., ... & Lok, S. M. (2020). Structural basis of Chikungunya virus inhibition by monoclonal antibodies. Proceedings of the National Academy of Sciences, 117 (44), 27637-27645.
Morrone, S. R., Chew, V. S., Lim, X. N., Ng, T. S., Kostyuchenko, V. A., Zhang, S., ... & Lok, S. M. (2020). High flavivirus structural plasticity demonstrated by a non-spherical morphological variant. Nature communications, 11 (1), 1-10.
Zhang, S., Loy, T., Ng, T. S., Lim, X. N., Chew, S. Y. V., Tan, T. Y., ... & Lok, S. M. (2020). A human antibody neutralizes different flaviviruses by using different mechanisms. Cell Reports, 31 (4), 107584.
Tan, T. Y., Fibriansah, G., Kostyuchenko, V. A., Ng, T. S., Lim, X. X., Zhang, S., ... & Lok, S. M. (2020). Capsid protein structure in Zika virus reveals the flavivirus assembly process. Nature communications, 11 (1), 1-13.
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