RNF213, an enzyme that cells use to fight viruses, can be switched on by the energy molecule ATP—and researchers now want to learn how to flip that switch deliberately. This matters because standard antiviral drugs target viral proteins, which mutate rapidly and render treatments useless. By instead activating the cell’s own antiviral machinery, the approach could make it much harder for viruses to evolve resistance. The project also studies ZNFX1, a protein that detects incoming viral RNA; children born without it suffer severe, often fatal infections. If the work succeeds, it could lead to a new class of antivirals that work by boosting host defences rather than attacking the virus directly. ATP-like molecules are already used as medicines for viruses and cancers, so there is a clear path for developing similar compounds that activate RNF213. The growing expertise in RNA-based therapeutics, accelerated by mRNA vaccines, also opens the possibility of designing an RNA treatment that compensates for ZNFX1 deficiency in children with the genetic mutation. This is fundamental science with a clear translational horizon.
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Viruses commandeer cellular machinery to amplify their number and transmit to new hosts, and in some cases, to establish life-long infection. Cells contain protein machines that detect viral infections and stymie their replication by diverse means. Classical antiviral medicines typically target viral proteins. By reducing viral replication, these drugs provide strong and escapable selective pressures for viral evolution, inevitably resulting in drug failure. Antivirals that instead exploit host defence mechanisms represent an exciting alternative approach to antiviral design. In this project, we will explore the suitability of two recently characterised virus-regulating enzymes as potential antiviral targets. The first protein is called RNF213 and we have recently discovered that this enzyme is activated by the energy-rich molecule ATP. RNF213 has been described to influence the replication of diverse viruses, bacteria and intracellular, eukaryotic parasites, by unknown mechanisms. The second protein is called ZNFX1 and is known to detect diverse RNA-based viral genomes as they arrive in the cell. Children born with mutations in the ZNFX1 gene suffer acute viral infections and hemophagocytic lymphohistiocystosis-like disease, an immunodeficiency resulting in multi-organ failure. The first aim of our project is to explore the chemical manipulation of RNF213 to invoke broad antimicrobial defence. We will look for ATP-like regulators of RNF213 and develop means to alter its function through the delivery of these molecules into cells. Our second aim is to understand the molecular features of viral genomes that are recognised by ZNFX1. We will explore whether RNA-based therapeutics can be designed to affect ZNFX1 function and specificity in cells. The potential applications of this work include the optimisation of ATP-like molecules that selectively bind and activate/inactivate RNF213, in collaboration with medicinal chemists and structural biologists. In fact, many medicines against both viruses and cancers are ATP-like molecules, meaning there is precedent for their successful administration to people. Investment in understanding RNA-based therapeutics has also grown considerably since the success of mRNA vaccines against COVID-19, and the means to develop such medicines are now widely available. A future benefit of this work could be the design of an RNA that ameliorates some of the disease associated with paediatric ZNFX1 mutation.
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