An international team of researchers has tested more than 10,000 compounds to identify six drug candidates that may help treat COVID-19.
The research, involving University of Queensland scientist Professor Luke Guddat, tested the efficacy of approved drugs, drug candidates in clinical trials and other compounds.
“Currently there are no targeted therapeutics or effective treatment options for COVID-19,” Professor Guddat said.
“In order to rapidly discover lead compounds for clinical use, we initiated a program of high-throughput drug screening, both in laboratories and also using the latest computer software to predict how different drugs bind to the virus.
Professor Guddat said the project targeted the main COVID-19 virus enzyme, known as the main protease or Mpro, which plays a pivotal role in mediating viral replication.
“This makes it an attractive drug target for this virus, and as people don’t naturally have this enzyme, compounds that target it are likely to have low toxicity.
“We add the drugs directly to the enzyme or to cell cultures growing the virus and assess how much of each compound is required to stop the enzyme from working or to kill the virus.
“If the amount is small, then we have a promising compound for further studies.”
After assaying thousands of drugs, researchers found of the six that appear to be effective in inhibiting the enzyme, one is of particular interest.
Six of these compounds inhibited Mpro with IC50 values ranging from 0.67 to 21.4 μM.
Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specifc drugs or vaccines are available.
The MS/MS data shows that ebselen, PX-12 and carmofur are all able
to covalently bind to C145 of the catalytic dyad in COVID-19 virus Mpro.
However, while PX-12 and carmofur completely modified Mpro, ebselen could only partially modify this viral cysteine protease.
Since ebselen has even stronger inhibition than the others, there
is a possibility that ebselen could also inhibit Mpro through non-covalent binding. It is likely that a portion of the hits identified by screening are covalently bonded to the catalytic cysteine of Mpro through their sulfhydryl groups.
In general, such molecules are expected to be promiscuous binders and therefore, as they stand, may have limited potential as drug leads. Since our structural data is based on N3, was investigated if
molecular docking could predict how disulfiram, tideglusib and shikonin bind to this protein. In all cases, reasonable docking poses were found, demonstrating that they could fit inside the substrate-binding pocket.
“We’re particularly looking at several leads that have been subjected to clinical trials including for the prevention and treatment of various disorders such as cardiovascular diseases, arthritis, stroke, atherosclerosis and cancer,” Professor Guddat said.
“Compounds that are already along the pipeline to drug discovery are preferred, as they can be further tested as antivirals at an accelerated rate compared to new drug leads that would have to go through this process from scratch.”
After the enzyme’s structure was made public, the team received more than 300 requests for more information, even before the paper was published.
“To provide an analogy, we’ve provided scientists with a fishing pole, the line and the exact bait, and have in only one month caught some fish,” Professor Guddat said.
“Now it’s up to us and the other fisherman – our fellow scientists globally – to take full advantage of this breakthrough.”
“With continued and up-scaled efforts we are optimistic that new candidates can enter the COVID-19 drug discovery pipeline in the near future.”
The international collaboration was led by researchers at ShanghaiTech University.
The research has been published in Nature (DOI: 10.1038/s41586-020-2223-y).