Research sheds light on how encapsulated viruses hijack protein production systems

Reviewed by Emily Henderson, B.Sc.November 6, 2020

Researchers from the universities of Melbourne, York, Warwick and Oxford have shed light on how encapsulated viruses such as hepatitis B, dengue and SARS-CoV-2 hijack the production and distribution pathways of proteins in the cell – they have also identified a potential anti-target of viral drugs to stop them on their trail.

The findings were published today in PNAS and are important for efforts to develop broad-spectrum antiviral agents.

Professor Spencer Williams of Bio21’s School of Chemistry said the research will help define a new “host-directed” approach to treating encapsulated virus infections.

One approach to treating viral infections is to create a new drug for each virus that presents itself. But it’s slow. An alternative and attractive approach is to create a drug against a human target for the viruses to replicate. The same drug can then be used and reused against many different viruses, even those that have yet to emerge. “

Professor Spencer Williams, School of Chemistry, University of Melbourne

The results come from the work of Professor Gideon Davies and his British team who elucidated how the structure of the catalytic domain of the human enzyme that cuts sugar molecules from proteins during their production and Professor Williams and his Bio21 team , who have developed a series of inhibitors to block the enzyme.

When tested on human cell lines, these inhibitors have been shown to reduce infection in dengue viruses.

‘Encapsulated viruses tend to exploit the’ glycosylation ‘phase of protein production, in which glycans or sugar molecules coat newly assembled proteins,’ said Professor Williams.

“The sugar molecules provide instructions for the proteins to fold into their correct 3D structure, as well as transport instructions for the protein to take to its next destination within the cell. Glycosylation is facilitated by various enzymes that synthesize, cut , they control and modify these sugar molecules. “

The cells in our body contain around 42 million protein molecules. Protein production is a complex, multi-step process within the cell. Like products on a factory assembly line, all proteins pass through “quality” control points where they are inspected before being transported to their destination to perform their functions.

Viruses are not living organisms, but biological programs encoded in ribonucleic acid (RNA) or deoxyribonucleic acid (DNA).

They come to life when they enter a living cell and hijack protein production systems. Viruses use the cell’s machinery to copy their DNA or RNA (in the case of SARS-CoV2, it’s RNA) and to make the proteins they need to make copies of themselves.

Viral proteins produced in an infected cell undergo “glycosylation” and then go through the steps of quality control, which involves “cutting” by an enzyme called “MANEA”.

“Trimming is a crucial step in quality control and when it does not occur, the client’s proteins are marked for degradation. MANEA represents a key target for developing broad spectrum drugs against encapsulated viruses, as inhibitors they will trigger the destruction of their proteins, ‘said Professor Davies.

As viruses hijack this unusual biosynthetic pathway, they make it a good potential drug target.

Researchers at the University of Warwick and the University of Oxford studied the effect of the best inhibitors on viral replication.