Viruses are terrible houseguests. They expect you to provide all the enzymes and proteins they need to make copies of themselves when they come for a stay in your cells. That leaves little to target with antiviral drugs, which is one of the main reasons it’s so difficult to make new ones.
But, in a development that sounds straight out of a sci-fi novel, scientists from the University of Cambridge have developed synthetic enzymes that could circumvent those challenges by targeting the genomes of viruses and cutting them into pieces, killing them. The “programmable molecular scissors,” as their creators describe them, can be quickly customized against different types of viruses—and, according to the results of a study published Nov. 16 in Nature Communications, they work on SARS-CoV-2, the viruses that causes COVID-19.
“We live in an era where it is now possible to sequence viral genomes within hours. For rapidly emerging pathogens, we need systems in place to design and synthesize precision medicines based on that information as quickly as possible,” Alex Taylor, Ph.D., corresponding author, told Fierce Biotech Research in an email. “Our work shows that with further development, reprogrammable XNAzymes like these have the potential to be a powerful platform for generating bespoke antivirals.”
The study serves as proof of concept for the enzymes, which Taylor and his colleagues initially developed from XNA—synthetic DNA and RNA—back in 2014. Dubbed “XNAzymes,” they work by recognizing and cutting sequences of nucleotides, the building blocks of RNA. They’re reportedly so precise that they won't cut RNA if even a single nucleotide differs from the programmed sequence. And, because the platform’s core structure remains the same regardless of what sequence is targeted, new XNYzymes can be created quickly. This makes it ideal for tackling mutating viruses.
“It’s like having a pair of scissors where the overall design remains the same, but you can change the blades or handles depending on the material you want to cut,” Taylor explained in a press release.
The first XNAzymes the lab created were designed to target Ebola, but, before they could be tested in live virus, the pandemic hit. Taylor’s team pivoted to testing whether they could work against COVID-19 instead. As soon as the RNA sequence of the SARS-CoV-2 virus was published, they scanned it for sequences their XNAzymes could attack.
The scientists swapped out the RNA sequences that were specific to Ebola with some for SARS-CoV-2, being careful to use parts of the genome that were less prone to mutation. They also pieced together three different XNAzymes to build a compound, or nanostructure, that could hit the genome at multiple places. This served as another safety net against mutations; the virus would have to mutate at multiple sites at the same time to evade the treatment.
With the XNAzymes assembled, it was time to pit them against COVID-19. First, the scientists tested them in artificial conditions with just SARS-CoV-2 RNA to ensure they were capable of cleaving it. Once this worked, they moved to cells incubated with live virus. Using a method called electroporation, they forced the XNAzymes into bioluminescent cells that would glow when they became infected with SARS-CoV-2, then incubated them with the virus. The luminescence of the infected cells containing the nanostructures was about 75% lower than those without them, and further studies measuring the amount of viral RNA showed that the XNAzymes had inhibited infection.
While the initial results are promising, much work remains. The study was meant to show that the XNAzymes were capable of cleaving their targets and inhibiting SARS-CoV-2, but the scientists still need to figure out how they’re going to get them into cells in the first place; electroporation, the technique they used to force them in, isn’t something that can be used clinically, Taylor explained. But they have options, such as linking them to lipids.
“Indeed, the mRNA COVID-19 vaccines were delivered using lipid nanoparticles,” he wrote, adding that inhalation into the lungs in small amounts might be another option.