Pillar 10 Antiviral Team Reflects on Three Years of Breakthrough Research

It has been an eventful three years for CoVaRR-Net’s Pillar 10 – Antiviral Strategies and Antiviral Therapeutics – team.

Led by Dr. François Jean, Associate Professor of Virology, Department of Microbiology and Immunology at the University of British Columbia and Founder of UBC’s Facility for Infectious Disease and Epidemic Research (FINDER), Pillar 10 has made significant strides in antiviral research. Its main objective has been to identify and profile the effectiveness of leading antivirals, alone or in combination with other compounds, against emerging SARS-CoV-2 variants and other human viruses with pandemic potential.

“We’re trying to apply a methodology that has been successful against some of the most notorious viruses such as HIV and hepatitis C, but in this case, against SARS-CoV-2,” says Dr. Jean.

One of its standout successes, garnering global attention, was its ground-breaking discovery of natural products for developing pan-SARS-CoV-2 therapeutics. The team investigated a catalogue of more than 350 compounds derived from natural sources including plants, fungi, and marine sponges in a bid to identify new antiviral drugs to treat COVID-19 variants such as Omicron. They identified 26 compounds that completely reduced SARS-CoV-2 viral infection, three of which were able to prevent SARS-CoV-2 infection in human lung cells. One of those was a sea sponge found in British Columbia.

“Teams, including ours, have looked into using known drugs to treat SARS-CoV-2,” says Dr. Jean. “But we’ve also highlighted the importance of looking at complementary sources of antimicrobials within natural products to really see a full therapeutic effect.”

Among the natural compounds screened, one out of five exhibited promising anti-SARS activity, showcasing a 20% success rate — an outcome that surpasses industry standards. Furthermore, the team’s exploration of already approved drugs and artificial intelligence-driven compound screening highlights their multifaceted approach toward drug discovery.

Another major Pillar 10 discovery was a new molecule shown to block SARS-CoV-2 that could be developed as a nasal spray drug for COVID-19. A joint effort between Dr. Jean’s team at UBC and Hector Aguilar-Carreno from Cornell University, as well as Drs. Richard Leduc and Pierre-Luc Boudreault from Université de Sherbrooke, the specially designed compound, named N-0385, blocks a particular human enzyme’s activity, used by the virus to infect a host cell.

“N-0385 represents an important potential addition to our arsenal in the fight against COVID-19,” says Dr. Jean.

A few single daily doses of N-0385, delivered via the nose, significantly improved clinical outcomes and the survival of genetically engineered mice infected with SARS-CoV-2, without detectable toxic effects. Protection was also demonstrated on cultured human lung cells and organoids (near-human infection models). The team tested the compound against variants Alpha, Beta, Gamma, and Delta, but the study was performed before the discovery of the Omicron variant.

More recently, Pillar 10 researchers investigated the effects of short administrations of the popular anti-COVID drug Remdesivir (RDV) on moderately ill hospitalized COVID-19 patients in Ontario. The goal was to find a way to reduce drug resistance in these patients who needed the treatment for a long time. The team found that the short courses of treatment did not cause drug-resistant mutations. It emphasized the importance of ongoing surveillance to maintain low mutation frequencies and preserve RDV’s efficacy against SARS-CoV-2.

Dr. Jean and the Pillar 10 team remain resolute in their dedication to advancing antiviral research despite encountering challenges, such as the time-constrained nature of funding cycles and the perpetual pursuit of financial support as CoVaRR-Net funding is in its last year.

Dr. Nathalie Grandvaux, Antiviral Strategies & Antiviral Therapeutics Pillar 10 Deputy and Professor in the Department of Biochemistry and Molecular Medicine at the Université de Montréal highlights how bringing experts from across Canada together under the CoVaRR-Net banner helped the development of novel antiviral strategies in Canada.

“It has been instrumental for us to be able to perform research on drug synergism and the impact on the variants of SARS-CoV-2. The numerous discussions with Pillar 10 members and members of other Pillars have allowed us to come up with better research design and tools,” says Dr. Grandvaux.

“Aiding each other, pooling expertise and working together was essential once we realized that vaccines were not offering a perfect solution.”

The World Health Organization (WHO) has urged countries to endorse a new document signalling their commitment to pandemic preparedness. It has composed a list of nine pathogens of concern that could jumpstart the next global pandemic. Dr. Jean says that opens up bioethical questions about vaccine and drug accessibility, especially with disparities persisting in vaccine distribution among some countries. He’s hoping the molecules that Pillar 10 helped discover and develop will be the first of their kind used against the priority pathogens on the WHO list.

“We’re pushing the boundaries now,” he says. “On the list of nine viruses listed by the WHO, we have researched five of them. What we’ll soon be doing is sending our small molecules to Biosafety Level 4 labs around the world to have them test our small molecules against those deadly viruses that only a few labs around the world can handle.”

The past three years have marked a period of significant achievement and international collaboration for Pillar 10’s researchers. With their sights set on expanding the impact of their discoveries to tackle a broad spectrum of viral pathogens, their antiviral research will leave a lasting impression on the global stage.