Summary: Six potential drug candidates have been identified as candidates to treat COVID-19 infections. The drugs, which have previously been subjected to clinical trials for treating a range of conditions, from arthritis to cancer, target Mpro, the main SARS-CoV-2 enzyme.
Source: University of Queensland
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.
“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.”
Source: University of Queensland Media Contacts: Luke Guddat – University of Queensland Image Source: The image is credited to Professor Luke Guddat.
Original Research: Closed access “Structure of Mpro from COVID-19 virus and discovery of its inhibitors”. Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, Yinkai Duan, Jing Yu, Lin Wang, Kailin Yang, Fengjiang Liu, Rendi Jiang, Xinglou Yang, Tian You, Xiaoce Liu, Xiuna Yang, Fang Bai, Hong Liu, Xiang Liu, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Chengfeng Qin, Zhengli Shi, Hualiang Jiang, Zihe Rao & Haitao Yang. Nature doi:10.1038/s41586-020-2223-y.
Structure of Mpro from COVID-19 virus and discovery of its inhibitors
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. 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 specific drugs or vaccines are available.