In human lung cells, donor-derived lung organoids, and “humanized” mice, a newly developed small-molecule drug candidate was shown to inhibit SARS-CoV-2 infection. The drug candidate, N-0385, looked especially promising in experiments with the humanized mice. When N-0385 was administered intranasally, it helped prevent COVID-19 in mice that were subsequently exposed to any of four variants of concern. N-0385 also provided effective treatment when it was administered up to 12 hours after exposure.
The new findings, which come from research conducted at the University of Sherbrooke, Cornell University, and the University of British Columbia (UBC), appeared in the journal Nature, in an article titled, “A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic.”
As the article’s title indicates, N-0385 targets TMPRSS2, a type-II transmembrane serine protease. TMPRSS2 is believed to play an essential role in the virus lifecycle by cleaving the viral spike protein and exposing the fusion peptide for cell entry.
TMPRSS2 is present in nasal cells, where the virus tends to enter, making a nasal spray the most practical and effective way to administer the compound. In addition, no mutations relating to the virus which causes COVID-19 have been found in this enzyme’s mechanism so far, as has occurred with other enzymes and COVID-19 variants, making it a useful target for defense against future strains of the virus, noted François Jean, PhD, a UBC researcher and a co-senior author of the Nature paper.
“In Calu-3 cells, [N-0385] inhibits entry of SARS-CoV-2 [variants of concern], B.1.1.7, B.1.351, P.1, and B.1.617.2,” the article’s authors detailed. “Importantly, in the K18-human ACE2 transgenic mouse model of severe SARS-CoV-2 disease, we found that N-0385 affords a high level of prophylactic and therapeutic benefit following either multiple or even a single administration.”
The researchers introduced N-0385 intranasally into the mice before, during, and/or after infection. Then they assessed how well the mice responded by tracking various clinical and pathological indicators, which included temperature, weight loss, histological signs of infection in tissue samples, and mortality. Ultimately, the researchers determined that N-0385 helped prevent weight loss, histological signs of infection, and death.
“Weight loss and survival data indicate that mice receiving N-0385 exhibited greatly reduced morbidity and mortality compared to untreated mice,” the article’s authors reported. “In addition to the reduced mortality, morbidity, and histological signs, immunohistochemical analysis indicated a significant reduction of SARS-CoV-2 nucleocapsid protein in the lungs and brain in the mice that survived. This is indicative of the effective reduction of virus propagation.”
Very few, if any, small-molecule antivirals have been discovered that work prophylactically to prevent infection, noted Hector Aguilar-Carreno, PhD, a Cornell researcher and a co-senior author of the Nature article. “This is the first of its kind,” he said of N-0385. “One advantage is that it works early in the infection, even after someone has already acquired the virus.”
In the current study, N-0385 was tested against alpha, beta, gamma, and delta variants. According to Jean, unpublished results from his team suggest that N-0385 is also effective at blocking omicron variant infections in human lung cells.
Jean asserted that N-0385 has the potential to be used as a broad-spectrum treatment against other viruses, including influenza viruses such as influenza A, H1N1, and influenza C. “Even not knowing what you’ve been infected with during flu season, you could potentially be prescribed a nasal spray to treat coronaviruses and the flu.”
He added, however, that the spray should be used in combination with other drugs already on the market, as the compound is an entry inhibitor, blocking entry of the virus to cells while other drugs reduce replication.
“The big picture is, there are multiple steps in the life cycle of a virus,” he explained. “The first step is entering a cell to pass on genetic material, then it goes on to replicate. So, you would use both drugs: N-0385 could block most of the virus’s entry, making less work for the replicator drug.”