2020 is already turning out to be another terrible year for dengue. The Pan America Health Organization is reporting all four dengue serotypes circulating in Guatemala, Mexico, Columbia and Brazil, significantly increasing the risk of severe infections. We recently explored why the ideal dengue vaccine has to neutralise all four dengue serotypes. Equally, scientists need to design new drugs that can inhibit all four dengue serotypes. Let’s take a look at one recent breakthrough.
Industry experts say there is currently no specific treatment or vaccine available for fighting dengue: “The only existing means of fighting the disease are the control of mosquito vectors in the regions concerned and individual measures to protect against mosquito bites,” according to the Pasteur Institute.
Several compounds – some repurposed from other diseases and others designed specifically for dengue – have been identified as potential treatments. Some have even been tested in clinical trials. None, however, has worked well enough to advance. There are a number of reasons why, with their struggle to treat all four dengue serotypes one key challenge.
Nevertheless, the search for possible dengue treatments continues. One recent example comes from a team of researchers at the University of Texas Medical Branch. They have been learning about the structure of the interior of the virus.
Meet the dengue capsid
The research investigates something called the ‘dengue capsid’. The capsid is found in all viruses, and is essentially a shell made up of proteins that surrounds the virus’ genetic material. In some viruses, including the dengue virus, the capsid is coated by a membrane known as an ‘envelope’.
The capsid is responsible for releasing a virus’ genetic material during infection. But before the dengue capsid can do this, the envelope coating the capsid must first be removed – a process known as ‘uncoating’. And if you can stop the ‘uncoating’ from happening, that might stop dengue in its tracks. The research aimed to reveal how a specific chemical compound – an inhibitor – might do just that.
The researchers discovered that the inhibitor can attach itself to a dengue capsid in a way that then binds four capsids together into something called a ‘capsid tetramer’ – with tetra simply meaning ‘having four’. A dengue virus containing the capsid tetramer then struggles to uncoat. Unable to uncoat, it is then unable to infect new cells.
Advancing our knowledge on dengue
Understanding the structure of the interior of the virus has also helped researchers grasp one reason why resistance to therapeutics can emerge. If the dengue virus mutates, it can weaken the inhibitor’s ability to bind to the viral capsid protein. If the binding doesn’t happen, the tetramer is not formed. And if the tetramer is not formed, the virus can uncoat. And if the virus can uncoat, it can continue infecting cells.
Their work focuses on a compound that stops the DENV2 virus in its tracks but is unable to fight DENV1, DENV3 or DENV4 dengue serotypes. They also identified the amino acids (essential organic compounds present in all our bodies) that prevent the inhibitor from binding to the capsids of other dengue serotypes. This might help identify compounds that can combat all four dengue serotypes.
The findings of this research are published in the Proceedings of the National Academy of Sciences. It has advanced our knowledge on how the different dengue serotypes function, uncovering potential new ways of fighting the virus. And while this is great progress, there is more work to do.