Coronaviruses are not new, they are a familiar threat of which no vaccines or antiviral drugs can prevent or treat infections in people; coronaviruses are a large group of viruses that are responsible for respiratory tract infections that range from the common cold to severe acute respiratory syndrome, Middle East respiratory syndrome, and now COVID-19.
Around the globe scientists are working hard to find antiviral agents that will be effective against SARS-CoV-2, and the ongoing global outbreak emphasizes the need for effective treatments and drug development.
While a lot of hope was placed on remdesivir which is an antiviral drug that was originally developed as a treatment for Ebola, recent clinical practice guidelines only give a weak recommendation for the drug in patients with severe COVID-19, and one study suggests that seaweed extract may be more effective.
Newer research published in the journal Science Translational Medicine has been focused on a group of antiviral compounds that target an essential enzyme in coronaviruses. According to the authors of the study the compounds drastically improved survival rates in mouse models of MERS and were observed to neutralize SARS-CoV-2 in cells from COVID-19 patients.
In the report the scientists from Wichita State University Kansas describe their research is based on the inhibition of 3C-like protease viral enzymes which is critical for the virus to replicate and thus survive, given this essential role the enzyme is known as the main protease.
The team specializes in making inhibitors of this enzyme and have previously developed the GC376 inhibitors that targets coronavirus infections in animals. The scientists showed that the compound could reverse the progression of severe feline infectious peritonitis: after a 2 week treatment period all cats receiving the drug made a full recovery.
In light of COVID-19 the team has directed their attention to coronaviruses in humans. As such they have synthesized a number of antiviral compounds with activity against a range of coronaviruses, and in the first round of testing the compounds were screened for antiviral activity against MERS-CoV, SARS-CoV, and SARS-CoV-2, examining the ability of the compounds to inhibit the 3C-like protease of the viruses in an isolated fashion as well as inside the cells. The protease has not yet been found in humans making it a good target for antiviral agents.
22 of the compounds that the scientists started off with were found to be of interest, in particular compound 6j was the most potent against SARS-CoV-2 compared to the other compounds tested. This compound was active against SARS-CoV-2 but it was particularly effective against MERS-CoV, at low concentrations.
These findings were confirmed in cells from the airways of those who had developed SARS-CoV-2 infections. Cells treated with the antiviral compounds were found to have had lower viral loads, indicating that the virus’s ability to replicate had been suppressed; the compound reduced viral replication by 10 times in cells from two patients, and in one patient the compound 6j was able to inhibit viral replication by 100 times.
At that time relevant mouse models of SARS-CoV-2 were still under development, but there was a mouse model of infection with MERS-CoV. Along with describing a possible treatment for SARS-CoV-2 the scientists also describe a possible treatment for MERS in this report, which continues to cause outbreaks with a fatality rate of around 35%.
The 6j compound was also able to inhibit the main protease of MERS-CoV: In animal testing all mice that were infected with MERS receiving the antiviral survived, and the treated mice fared better internally with lower viral loads and significantly less lung damage than those without treatment.
Although very promising, this preclinical research does not demonstrate efficacy in humans, additionally there are very marked clinical differences between SARS-CoV-2 and MERS-CoC infections in humans. However, this work has established proof of concept for the team that should allow them to build off of. As such the team plans to continue their research to determine if one of their compounds is capable of treating COVID-19 and MERS in humans.
