A novel coronavirus called SARS-CoV-2 (previously known as 2019-nCoV) is spreading widely and rapidly around the world. The disease of SARS-CoV-2 infection is termed Coronavirus Disease 2019 (COVID-19) by WHO. SARS-CoV-2 can cause severe acute respiratory symptoms and transmit in humans via respiratory droplets or contacting. The cumulative number of pneumonia deaths caused by SARS-CoV-2 is more than ten thousand. Unfortunately, there is no approved drug to treat human coronavirus. How to quickly find an effective strategy to treat COVID-19 is a major challenge for researchers. Who will be the “savior” of mankind?
In terms of time, research progress, safety and effectiveness, compared with monoclonal antibodies, oligonucleotide-based therapy, plasma therapy and other therapies, small molecular drugs are the best choice. First of all, new interventions may take months to years to develop, and in terms of time and current research progress, the most promising is small molecular drug therapy. Secondly, the existing antivirals have known safety characteristics and efficacy against coronaviruses, so the reuse of existing small molecular antiviral drugs (“new use of old drugs”) is an important and promising strategy to deal with SARS-CoV-2. If the existing drugs can be relocated and drugs for the treatment of SARS-CoV-2 infection can be found, we can bypass preclinical studies (such as animal experiments and pharmacological studies) and early clinical studies and enter clinical phase 2 or 3 directly. Finally, some small molecular drugs have broad spectrum.
From many existing compounds or databases, using the latest research methods, AI-assisted drug screening is an important means. The advantage of this strategy is that a large number of potentially active drugs can be obtained quickly through high-throughput screening, and the experimental data can also reflect the potential drug efficacy to some extent.
Yang Haitao’s team successfully expressed 3CL hydrolase (Mpro), a key protease of novel coronavirus, and obtained its crystal structure. According to the comparison of amino acid sequence, the similarity between novel coronavirus and SARS virus Mpro is 96%. Therefore, Mpro is used as an important target for drug screening against novel coronavirus. On this basis, the joint anti-coronavirus infection emergency public relations team of the Institute of Immunochemistry of Shanghai University of Science and Technology and Shanghai Institute of Medicine, Chinese Academy of Sciences, through computer virtual screening combined with enzyme detection, 30 drugs or compounds that may have therapeutic effects were found, including antiviral drugs such as Lopinavir, Darunavir, Cinanserin and Cyclosporin A.
The joint research team of Huazhong Science and Technology, Tongji Medical College of Huazhong University, Wuhan Children’s Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology, the first affiliated Hospital of Xi’an Jiaotong University, Beijing Genome Research Institute of the Chinese Academy of Sciences, and Huawei Cloud announced that five antiviral drugs that may be effective against 2019-nCoV have been screened. There are: Beclabuvir, Saquinavir, Bictegravir, Lopinavir, Dolutegravir. Among them, Beclabuvir may be a potential inhibitor of NSP12. Saquinavir and Lopinavir can bind not only to Mpro protein, but also to 2019-nCoV ‘s protein, thus preventing the binding of S protein and ACE2 receptor, so they can prevent the expansion of virus both inside and on the cell surface. Lopinavir has been listed in novel coronavirus’s clinical trials. Bictegravir and Dolutegravir are HIV virus integrase inhibitors that inhibit virus replication by blocking integrase.
ACE2 and TMPRSS2 are also the key targets of this drug screening, but there are no reports on the specific drugs for these two targets, and the drugs for the target of ACE2 are also under intensive testing. Currently, the results of ultra-large-scale computer-assisted drug screening by the joint team show that Saquinavir and Lopinavir may act on ACE2, to prevent the virus from binding to cells.
Through the ongoing global efforts to prevent and treat SARS-CoV-2 transmission and infection, it is further shown that the “new use of old drugs” can solve the urgent needs, and in order to prevent the re-attack of viruses with similar genomic and pathological characteristics a few years later, it is urgent to develop more specific, safe and effective drugs, and there is an urgent need to redevelop antiviral drugs to fight coronaviruses. It is hoped that many scientific researchers and relevant pharmaceutical companies and other personnel will make continuous efforts to solve this problem together.