December 2016 | Issue 27
LKCMedicine team identifies potential drug-target for Zika treatment

 

Living up to its name, the Zika virus ran wild this year – infecting hundreds of thousands of people from Brazil to Singapore. Meaning overgrown in the Luganda language spoken in central Uganda where the virus was first identified, it has spread rapidly despite the best efforts to contain and control this mosquito-borne disease.

Unlike its viral cousin dengue, the Zika virus attracted little attention from the research community for much of the 60 years following its discovery in Uganda’s Zika Forest. The infection, which is endemic in Africa and Asia, at first appeared to cause only mild symptoms with no serious consequences.

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Asst Prof Luo Da Hai, the man behind the discovery of the protein NS2B-NS3

It wasn’t until late 2015, that Zika virus caught the world’s attention. The huge numbers of people infected coupled with the emergence of alarming Zika virus-linked birth defects, such as microcephaly and serious conditions affecting the central nervous system, such as Guillain-Barre syndrome, made finally the scientific community take note.

Working against the clock, studies to develop vaccines, diagnostics and treatments for Zika virus, a relatively small virus consisting of three structural and seven non-structural proteins, were greenlighted by governments and research institutions.

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Crystal structure of the bZiPro, showing an electrostatic view of the structure

Now scientists at LKCMedicine have shed light on the protein which is essential for virus replication. This protein, called NS2B-NS3, is considered an ideal target for potential antiviral drug development as without it, the virus cannot multiply inside an infected host. These findings by the lab of Nanyang Assistant Professor Luo Dahai were published in the journal Science this month.

Using an artificial linker, usually a short string of amino acids, scientists could combine two proteins to study a specific process in great detail. Previous research on this key protein was largely conducted using this method.

Research Assistant Zhang Zhenzhen from Asst Prof Luo’s lab and the lead author of this paper said, “This artificial linker altered the inhibitor binding activity and this is not ideal when you are trying to identify suitable drug targets in a novel virus.”

Working with collaborators at A*STAR’s Experimental Therapeutics Centre and NTU’s School of Biological Sciences, the team chose not to use a linker. This allowed them to determine the structure of this protein in as close to a natural state during virus infection as is possible to create in the test tube.

While there is still a long way to go, the team is hopeful of finding an effective antiviral drug for Zika. Asst Prof Luo said, “Based on the pocket structure, we predict that certain cyclic peptides can bind to the active site of the NS2B-NS3 protein and inhibit its activity.”

What is even more exciting is that it may have implications for other viruses in the same family. Asst Prof Luo said, “This knowledge is translatable to dengue, West Nile virus, Japanese encephalitis and other flaviviruses.”