Summarize this content to 2000 words in 6 paragraphs Finding a new viral targetANSTO’s Australian Synchrotron can accelerate a beam of electrons to almost the speed of light and produce light one million times brighter than the sun.These super-tiny, super-bright “beamlines”, when fired at a molecule, can create a 3D snapshot of its structure. Professor David Komander, of Melbourne’s Walter and Eliza Hall Institute (WEHI), led a team of scientists in 2020 who used this method to identify the structure of a COVID-19 protein called PLpro.Antibodies binding the SARS-CoV-2 virus.Credit: Dr Drew Berry/WEHIPLpro is critical for a virus’s replication. It cleaves chains of amino acids into smaller foot soldiers that help the virus go on to infect more cells.PLpro’s cousin, a protein called Mpro, executes a similar function. The antiviral Paxlovid inhibits Mpro, which helps prevent severe sickness.LoadingBut PLpro has another critical function: it suppresses Type I interferons, which are molecules crucial to a cell’s defence against viral attack. Inhibiting PLpro could, therefore, stop the virus replicating and block its ability to bamboozle our immune response.After uncovering what PLpro looks like, scientists hunted through 400,000 chemical compounds at WEHI’s National Drug Discovery Centre to identify drug candidates that may block the protein’s function.They found one that worked. And its potential to subdue the development of long COVID, they say, is unprecedented.Blocking long COVIDModelling a disease with more than 200 symptoms is difficult. But a COVID-19 mutation arose by chance in 2020 which allowed the virus to better infect mouse cells. That gave scientists the chance to replicate severe disease, and long COVID, within living animals from a real strain rather than one that was genetically engineered.“We think it’s really one of the best models that closely mimics what you see in human long COVID patients,” WEHI’s Laboratory Head Dr Marcel Doerflinger says.“There’s a lot of damage in the lung, persistent inflammation and infiltration of immune cells, fibrosis, issues in the heart, in the gastrointestinal tract. They have cognitive impairment, they have issues with anxiety and depression.”When the scientists treated mice with the new PLpro-blocking compound at the acute phase of their infection – six hours for mice, equivalent to about three to five days into illness for a human – they could prevent severe disease better than Paxlovid could.And the compound also did something Paxlovid can’t: it prevented the onset of long COVID symptoms. “That was something no one else had shown before,” says Doerflinger.Doerflinger and his colleagues write in their new Nature Communications paper that the new compound may therefore be clinically relevant for the prevention and treatment of long COVID, although human studies are required to verify that claim.“Any way to protect against long COVID is great,” infectious disease researcher Professor Kirsty Short from the University of Queensland, who wasn’t involved in the study, says.“But perhaps the bigger question is, what do we do for people who are already living with long COVID?”Could antivirals reverse, as well as stop, long COVID?“The holy grail would be something to treat patients who have had long COVID already for a long time,” Doerflinger says. “I’m not sure this drug can do that.”LoadingOne leading theory of what causes long COVID holds that the disease is caused by reservoirs of the virus lurking and continuing to replicate within patients. Studies have reported prolonged viral shedding and COVID-19 RNA in people’s blood years after infection, lending support to the theory.That’s why scientists are investigating whether antivirals can treat, rather than just prevent, long COVID. Two recent studies into Paxlovid, however, found it didn’t improve long COVID symptoms in patients prescribed short courses of the drug.Another theory, Short says, is that long COVID is caused by fragments of the virus persisting in the body that spark up inflammation. If that’s the case, antivirals mightn’t help. The disease may also be caused by an imbalance in the gut microbiome or a haywire inflammatory immune response, or some combination of these theories.Short is one of the scientists behind a long COVID risk calculator. Running it for yourself can be pretty shocking – according to the calculator I had a greater than 50 per cent chance of at least one symptom hanging around after my next infection.Many of us might have moved on from worrying about COVID, but the risk of life-altering effects from your next bout of illness remains real, Short says.“This is a disease where we have no diagnosis, no treatment, no cure. And we really need to fix that.”Enjoyed Examine, our free weekly newsletter covering science with a sceptical, evidence-based eye? Sign up to get the whole newsletter in your inbox.
