Antiviral Strategies and Antiviral Therapeutics
Scientists, including some here in Canada, are contributing to the development of nasal-spray medications that would protect against numerous COVID-19 variants. One CoVaRR-Net-funded research team, led by CoVaRR-Net Pillar 10 Lead Dr. François Jean and including Drs. Andrea Olmstead, Ivan Robert Nabi, and Dr. Guang Gao, all from the University of British Columbia (UBC), has published recent findings in Nature, discovering a new molecule that could speed the creation of these nasal sprays. Their findings were made in collaboration with Associate Professor Hector Aguilar-Carreno at Cornell University and Drs. Richard Leduc, Éric Marsault, Pierre-Luc Boudreault and their team at Université de Sherbrooke.
The study hinges on a promising new molecule called N-0385, which has been shown to block the SARS-CoV-2 virus from entering human cells through its favoured cell gateways and appears to offer protection against severe illness and death. The manuscript describes how a few single daily doses of N-0385, delivered via the nose, significantly improved clinical outcomes and 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 models of infection).
Dr. Jean’s team at UBC’s Facility for Infectious Disease and Epidemic Research (FINDER) tested four variants of concern (VOCs), including Alpha, Beta, Gamma, and Delta, in human lung cells and organoids – tissue cultures that can mimic the organ they’re taken from – and found that N-0385 inhibits all SARS-CoV-2 VOC infections, with no evidence of toxicity. The study was conducted prior to the discovery of the Omicron variant.
The work appears to be the most effective entry inhibitor to date, with N-0385 – developed by the Université de Sherbrooke team – blocking a key enzyme, TMPRSS2. That enzyme is responsible for cutting and priming the viral protein so that it can attach and fuse with the host cell membrane, and release the virus’s genetic material.
The study also demonstrates that N-0385 is broadly protective against infection and mortality in mice, and Dr. Aguilar-Carreno’s team showed that N-0385 has potential as a viable early treatment option against emerging SARS-CoV-2 VOCs.
“My team recently demonstrated that N-0385 is also very effective at blocking Omicron variant infections in human lung cells. Our unpublished results represent encouraging findings with the current rapid propagation of the Omicron BA.2 subvariant around the world,” explains Dr. Jean.
Work in progress by Dr. Jean’s team at UBC will determine if N-0385 may possibly act synergistically when used in multi-drug combinations with recently FDA-approved antivirals for SARS-CoV-2 infection such as Remdesivir, Paxlovid, and Molnupiravir to reduce the risk of antiviral resistance mutations.
“N-0385 represents an important potential addition to our arsenal in the fight against COVID-19, in particular with its remarkable broad-spectrum antiviral activity against all the past and current SARS-CoV-2 variants of concern that have been tested thus far in my lab at UBC,” he adds.
Dr. Jean, who was a project lead for the study, is a professor of virology in the department of microbiology and immunology at UBC and Lead of Pillar 10 (Antiviral Strategies and Antiviral Therapeutics) at CoVaRR-Net. Dr. Jean’s studies on SARS-CoV-2 are performed at the UBC FINDER, one of the largest university-based containment level 3 (CL-3) facilities in the world that he founded in 2010.
Shapira, T., Monreal, I.A., Dion, S.P. et al. A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature (2022). https://doi.org/10.1038/s41586-022-04661-w