New study boosts prospects for first Zika treatments

Researchers have discovered an exciting novel function in the Zika virus – raising hopes of developing the world’s first treatment for the disease.

The findings show precisely how the Zika enzyme NS2B-NS3 acts as both a protease and a helicase: first dividing proteins, and then breaking up its own double-stranded RNA into single strands.

To do so, it cycles between what the US team calls ‘open’ and ‘super-open’ states that bind and then release the virus’s RNA into host cells.  

And the good news is that these shape shifts could potentially be blocked by small molecule drugs - meaning that targeting of NS2B-NS3 in the right way could prevent host production of disease-bearing Zika particles.

“We found that Zika's enzyme complex changes function based on how it's shaped,” said Alexey Terskikh, an associate professor at Sanford Burnham Prebys Medical Discovery Institute and senior author of the research.

“When in the closed conformation, it acts as a classic protease.

“But then it cycles between open and super-open conformations, which allows it to grab and then release a single strand of RNA - and these functions are essential for viral replication.”

In their research paper, published in the journal PLOS Pathogens, the Sanford Burnham Prebys team provides the first detailed breakdown of the complex molecular workings behind the NS2B-NS3 helicase-protease.

They found that, while in the ‘closed’ state, the protease part of NS2B-NS3 called NS2B-NS3pro performs its expected function of cutting long polypeptides into Zika proteins.

But it then binds single-stranded RNA with the help of two, positively charged, fork-like structures that are only present when it is in the ‘open’ configuration.

The enzyme then releases Zika RNA when ‘yanked’ into the ‘super-open’ conformation by its helicase part, NS3hel, pulling on a short amino acid linker.

The group has named the newly-discovered process the “reverse inchworm” since the whole cycle appeared to team members like a worm travelling backwards.

The researchers also believe that this worm-like mechanism is “likely to be a shared feature of all flaviviruses”: a genus that includes Dengue Fever, Yellow Fever, Japanese encephalitis, and West Nile virus, which the Centers for Disease Prevention and Control say “cause widespread morbidity and mortality throughout the world.”

To date, there is no effective treatment for the Zika virus – but, armed with this new and detailed knowledge, scientists may soon be able to design small molecule drugs that ‘freeze’ the workings of the Zika enzyme, as well as other Flaviviridae.

“Targeting the interface of the specific alignment of NS3pro and NS3hel domains proposed here with bivalent small molecules that can bridge NS3pro and NS3hel...  could be a universal and highly specific approach targeting the replication of (Zika virus) and flaviviruses in general,” the Sanford Burnham Prebys group states.

“It could potentially constitute a whole new class of drug targets for multiple viruses,” Professor Terskikh added.