Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals

Over the past 20 years, intense research efforts have focused on understanding and developing therapies for viruses with pandemic potential that have demonstrated the capacity to cross the species barrier, spread through respiratory routes, and lead to high hospitalization and mortality rates, such as coronaviruses and influenza viruses. Despite the pandemic concerns of emerging coronaviruses, the world was caught off guard and immeasurably devastated by the COVID-19 pandemic. Even with the success of current COVID-19 vaccines, many issues remain, such as the continuous emergence of highly immune-evasive SARS-CoV-2 Omicron subvariants and the potential emergence of further variants that could render existing treatments ineffective.

The host-directed anti-viral, N-0385, is a broad-acting nanomolar antiviral against highly immune-evasive SARS-CoV-2 subvariants. The results in this publication suggest that a multi-targeted treatment based on N-0385, a host-directed TMPRSS2 inhibitor, could lead to therapeutic benefits when used in combination with viral replication inhibitors (either remdesivir or nirmatrelvir) both by enhancing treatment efficacy and by avoiding the development of monotherapy resistance.  This work was funded by CoVaRR-Net (Dr. Francois Jean, University of British Columbia) and Canadian Institutes of Health Research (Dr. Francois Jean, UBC, and Dr, Richard Leduc and Dr. Pierre-Luc Boudreault, Université de Sherbrooke).

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