Researchers may have found a way to neutralise the deadly pox family of viruses through the structural analysis of a protein that provides, for the first time, a clear target for antiviral drugs able to block virus assembly.
They have also found that this protein, D13, represents an evolutionary link with other viruses infecting all kingdoms of life and opens the possibility of a whole new class of drugs to treat viral infections.
In 2011, Dr Fasséli Coulibaly from Monash University’s Department of Biochemistry and Molecular Biology and Associate Professor Alok Mitra from the University of Auckland discovered that D13 is related to structural proteins found in many large DNA viruses. The significance was immediate – a target for the development of inhibitor drugs able to block the formation of all poxviruses and the infections they cause.
“Because D13 is common to all poxviruses, the potential exists to develop antiviral drugs that are effective against a whole family of viruses, similar to the effect of antibiotics on bacteria,” Dr Coulibaly says.
The best known of the poxviruses is smallpox, which killed millions of people a year before it was eradicated through a global vaccination program in the late 1970s. Only two official, highly secure stocks remain (in the US and Russia), leaving humanity now with only a small risk of deliberate release through an act of war or bioterrorism.
It is other members of the poxvirus family that are causing concern. Many of these, including monkeypox (closely related to smallpox), have the capacity to jump species and infect humans. Dr Coulibaly and his team are working hard to develop and test D13 inhibitors as a potential basis for new antiviral drugs. He says that since routine smallpox vaccination was discontinued in the 1980s, population immunity to poxviruses has waned – and periodic outbreaks of monkeypox have been recorded in the Congo Basin, West Africa and Sudan.
Monkeypox is mostly transmitted to humans from rodents and primates; however, Dr Coulibaly says a non-fatal outbreak among carers of pet prairie dogs in the US in 2003 was a reminder of how quickly viruses can spread, away from the usual epidemic regions. The prairie dogs had come into contact with infected rats and squirrels imported from Ghana, West Africa.
Dr Coulibaly says poxviruses are a large and diverse family of viruses, and at a molecular level relatively little is known of their complex structure and assembly. This lack of knowledge has made it difficult for drug development. The Monash team is improving understanding of how molecules produced by infected host cells combine to form an infectious virus particle.
By targeting D13, researchers hope to find a way to use it to ‘sabotage’ the virus’s ability to join up with other viral molecules to trigger this infectious cycle. Because of D13’s presence in all poxviruses, it holds the promise of wider therapeutic potential. Dr Coulibaly’s team was recently awarded a three-year National Health and Medical Research Council grant to take this science further.
Dr Coulibaly says D13 has been studied for a long time but no one has previously been able to look at how it functions in atomic detail. “Using a combination of X-ray crystallography at the Australian Synchrotron and electron microscopy at the University of Auckland, we were able to produce a 3-D model of the D13 layer covering immature virus particles.”
The structure resembles a honeycomb scaffold that is involved in the early assembly steps before any infectious particle is formed. Targeting this structure opens the opportunity to design broad-spectrum antiviral drugs able to quickly limit any future poxvirus outbreak.
