New drug can prevent and treat infection of various COVID-19 mutant strains

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New drug can prevent and treat infection of various COVID-19 mutant strains

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New drug can prevent and treat infection of various COVID-19 mutant strains. 

Nature: New coronavirus broad-spectrum specific drugs for new targets, without fear of mutation, can prevent and treat infection of various mutant strains

The COVID-19 pandemic has raged across the globe for more than two years, infecting hundreds of millions and killing millions. With the increase in the number of infected people, today’s new coronavirus (SARS-CoV-2) has accumulated a large number of mutations and evolved into Delta and Omicron , which are more infectious and have immune escape ability. variant strain.

However, it should be noted that most of the existing COVID-19 vaccines are developed based on the original virus strains of the COVID-19, and the effectiveness of these COVID-19 variants is constantly decreasing. Therefore, the COVID-19 pandemic is likely to remain a global health threat for the foreseeable future.

In response to emerging Covid-19 variants, developing a broad-spectrum Covid-19 treatment will be key to containing the COVID-19 pandemic.

Recently, researchers from Columbia University and Cornell University published in Nature titled: A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic (TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic and therapeutic drugs) .

The research developed a small molecule compound that inhibits TMPRSS2 , N-0385 , which can prevent the infection and invasion process of the new coronavirus and its variant strains (including Delta and Omicron) .

More importantly, N-0385 provided high levels of prophylactic and therapeutic effects after multiple or single intranasal administration in an ACE2 transgenic mouse model capable of SARS-CoV-2 infection.

The life cycle of SARS-CoV-2 begins with attachment and entry into respiratory epithelial cells via angiotensin-converting enzyme 2 (ACE2) receptors.

It is worth noting that the spike protein (S protein) of the new coronavirus also needs to hijack the host’s type II transmembrane serine protease, such as TMPRSS2 , before mediating the fusion of the virus with the host cell membrane. of the S protein to help it enter the host cell.

To put it vividly, if ACE2 is compared to a ” door handle “, then TMPRSS2 is ” lubricating oil “. With the help of TMPRSS2 and ACE2, SARS-CoV-2 can successfully invade human cells. This also implies that TMPRSS2 is a potential therapeutic target for preventing SARS-CoV-2 infection.

In this latest study, the research team developed a small library of peptidomimetic compounds to screen for inhibitors of TMPRSS2 proteolytic activity.

Through a series of screening and functional verification, the researchers found an optimal peptidomimetic compound – N-0385 , this small molecule compound can inhibit TMPRSS2 by 83%, much higher than the clinically approved TMPRSS2 inhibition camostat mesylate (53%) .

Research team screened peptidomimetic drugs that inhibit TMPRSS2

In in vitro cell experiments, the inhibition rate of N-0385 against SARS-CoV-2 infection can reach 99% , its half effective concentration (EC50) is 2.8±1.4nM, and it does not show any cytotoxicity. In contrast, the EC50 of camostat mesylate was 10.6 ± 8.4 nM.

More importantly, N-0385 has strong anti-infective efficacy against several common SARS-CoV-2 variants such as Delta and Omicron .

In fact, no TMPRSS2-related mutations have been found in the existing SARS-CoV-2 variants, suggesting that N-0385 is likely to be a broad-spectrum antiviral drug that can target multiple SARS-CoV-2 variants.

Anti-TMPRSS2 peptidomimetics such as N-0385 are low nanomolar inhibitors of SARS-CoV-2

Subsequently, the research team further tested the therapeutic effect of N-0385 in an ACE2 transgenic mouse model capable of infecting SARS-CoV-2. The study showed that intranasal administration of N-0385 significantly reduced morbidity and mortality in infected mice: in the lungs of N-0385-treated mice, SARS-CoV-2 was reduced by 97% and 98%, respectively, after 3 days; 8 days In the N-0385 treatment regimen, 70% of the mice were protected from death from SARS-CoV-2 infection.

N-0385 reduces infection and improves survival in mice

Not only that, the surviving mice treated with N-0385 were in better physiological state, with tissue morphology tending to be pre-infection. These data demonstrate that N-0385 has strong antiviral efficacy even in animal models.

In addition, the research team also confirmed that for the COVID-19 Delta variant, N-0385 has the same powerful effect in protecting mice from infection.

N-0385 has inhibitory effect on four new coronavirus variants

Overall, the study reports an inhibitor targeting TMPRSS2, N-0385 , a peptidomimetic drug that blocks a key step in viral invasion, effectively inhibits 2019-nCoV infection, and reduces SARS-CoV-2 infection in mice. infection rates, improved survival, and improved treatment outcomes.

More importantly, N-0385 has good anti-infective efficacy against various new coronavirus variants (such as Delta and Omicron) , providing a new and effective prevention and early treatment for the infection of the new coronavirus and its variants choose.

Reference :
https://www.nature.com/articles/s41586-022-04661-w

New drug can prevent and treat infection of various COVID-19 mutant strains

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