Scientists use original approach to solve 3D structure of flaviviruses

In a recent study, Australian scientists used an original approach to solve the 3D structure of flaviviruses with an unprecedented level of detail, identifying small molecules called “ pocket factors ” as new therapeutic targets.

Flaviviruses infect humans through mosquito or tick bites, with symptoms ranging from fever and myalgia to life-threatening neurological and congenital conditions. Flaviviruses such as dengue, yellow fever and Zika virus threaten nearly a third of the world’s population, and new flaviviruses regularly emerge from animal reservoirs that can cause epidemics.

There is currently no approved antiviral drug for flavivirus infection, and most flaviviruses do not have a vaccine. The structures of infectious particles are essential for mapping the vulnerabilities of the viral outer surface in order to design better therapies. However, determining the structure of highly pathogenic flaviviruses is only possible in very few places around the world where microscopes are contained in high biosecurity environments.

In the study, published in Nature communications, a team led by Associate Professor Fasséli Coulibaly of Monash University and Associate Professor Daniel Watterson of the University of Queensland, generated three new flavivirus structures using an approach that does not require the same level of containment.

This approach takes advantage of a single flavivirus first isolated from mosquitoes in the Binjari region. The virus has no known vertebrate – specifically human – host, which makes it easy to handle without the risk of human infection. The researchers used the Binjari virus as a platform to produce benign chimeric viruses with an outer envelope of medically relevant viruses.

The team used the Ramaciotti Center for Cryptographic Microscopy at Monash University to determine the structures of chimeric particles. They found that these viruses mimic the infectious particles of several pathogenic flaviviruses in great detail. This provides a universal path to the safe and rapid determination of the structure of existing and emerging flaviviruses.

Because the structural proteins are derived from the virus infecting humans, the particles resemble the pathogenic virus. This means that we can determine the structure of these proteins in a native context and that these particles can be used for vaccine and diagnostic purposes. “

Daniel Watterson, Associate Professor, University of Queensland

ability to visualize water molecules and tiny pocket factors nestled in infectious particles.

“Due to the impressive resolution of our structures, we were able to build accurate models for these viruses. We saw how pocket factors bind to conserved parts found in all pathogenic flaviviruses. Their location suggests that they might be the final pivot to ensure the infectious particle is securely attached before it leaves the cell, ”he said.

This study builds on the progress made by the research team in understanding the maturation of flaviviruses recently published in Scientific progress. Together, the studies identify the adoption of pocket factors as a potential target for the design of broad-spectrum therapies.