Harnessing a natural blood vessel molecule to develop broad mRNA antivirals

In a surprising discovery, a 'sticky molecule' that occurs naturally in our blood vessels could be both a culprit behind blood clots and organ failure during COVID and long COVID and the key to new treatments to counter COVID-related viruses.

Researchers say the molecule, called P-selectin, could turn the tide to develop a new generation of mRNA therapies to combat not just COVID variants, but also other viruses in the same family.

The study, co-led by the Charles Perkins Centre at the University of Sydney, was published in the Journal of Clinical Investigation. 

P-selectin is a molecule that already plays a major role in inflammation in our body, acting like a homing signal to immune cells during infection. 

The study found that P-selectin was especially 'sticky' and attached itself readily to protein 'spikes' on the surface of coronaviruses, SARS-CoV-1, MERS-CoV, and both Wuhan and Delta strains of SARS-CoV-2 (the virus responsible for causing COVID).

""P-selectin is expressed on platelets – the cells that cause blood clots – and it promotes virus and platelet complexes that can cause dangerous blood clots, a major driver of death in severe COVID infection, and also a likely cause of long COVID," said lead researcher Dr. Cesar Moreno from the University of Sydney's Charles Perkins Centre and Faculty of Science.

But P-selectin also normally controls white blood cell migration through our body., and our study found that during COVID infection, P-selectin also captures SARS-CoV-2 virus in the blood, holding the virus in blood vessels and blocking its ability to infect our cells."

Importantly, when the researchers created an mRNA-based therapy that could drive P-selectin expression in the absence of inflammation, it provided broad protection against coronavirus infection.

"Since P-selectin can catch the virus and block its ability to infect our cells, we took advantage of this to create a broad-acting mRNA therapy that can protect against known and most likely emerging coronavirus pandemic strains," said Dr Moreno.

The researchers used CRISPR genetic screening to test the entire human genome, looking for any human genes that can block SARS-CoV-2 infection. Beyond P-selectin, they found 33 other new genes that can protect us from SARS- CoV-2, and these genes can likely also be used as protective therapies against coronavirus and probably also other major viral infections.

"Vaccines have significantly reduced disease severity and deaths, but whether it's coronavirus or other strains, at some stage new pandemics will pose a threat to us. Having broad, easily manufactured mRNA therapies ready can help mitigate these risks," said senior author Professor Greg Neely, Head of the Dr. John and Anne Chong Lab for Functional Genomics at the University of Sydney.

"In some cases people can't get vaccinated, and for these people our strategy can provide another source of protection from current or emerging viral threats,"

"We now have a realistic strategy to future-proof against the next pandemic."