Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening

Abstract

2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.

Structural and Evolutionary Analysis Indicate that the SARS-CoV-2 Mpro is an Inconvenient Target for Small-Molecule Inhibitors Design

“…The lack of success might be related to the above-mentioned plasticity of the binding cavity. Some of these compounds have been used for docking and virtual screening research aimed not only at SARS-CoV [42,43] but also at the novel SARS-CoV-2 [15][16][17][18][19][20][21]. Such an approach focuses mostly on the structural similarity between the binding pockets, but ignores the fact that the actual available binding space differs significantly.…”

“…Indeed, an in silico attempt has already been made involving a massive virtual screening for Mpro inhibitors of SARS-CoV-2 using Deep Docking [15]. Other recent attempts focused on virtual screening for putative inhibitors of the same main protease of SARS-CoV-2 based on the clinically approved drugs [16][17][18][19][20][21], and also based on the compounds from different databases or libraries [22][23][24]. However, none of such attempts is likely to lead to clinical advances in the fight against SARS-CoV-2 for reasons we elaborate below.…”

Recent progress in understanding 2019 novel coronavirus (SARS-CoV-2) associated with human respiratory disease: detection, mechanisms and treatment

“…These similarities give doctors and scientists a clue to look for targeted drugs. Although coronaviruses are subject to extensive mutations, some key proteins, particularly replication-related enzymes, are highly conserved [34] , so drugs targeting conserved proteases are usually able to block replication and proliferation of the virus and exhibit a broad spectrum [47] . Specific inhibitors of key proteases involved in viral replication and proliferation are effective ways of killing viruses.…”

“…Candidate compounds include RNA proteases, membrane proteins, spike glycoproteins, polymerases and viral envelope that act directly on the virus, as well as targets on the host such as receptors and proteases for virus entry and endocytosis [48][49][50] . Recently, scientists screened out four small-molecule drugs (prulifloxacin, tegobuvir, nelfinavir and bictegravir) with strong binding affinity to the main protease of SARS-CoV [47] . The first case of SARS-CoV-2-infected pneumonia in the USA experienced significant improvement in clinical symptoms after receiving an intravenous (i.v.)…”

Potential Inhibitors Against Papain-like Protease of Novel Coronavirus (COVID-19) from FDA Approved Drugs

“…Recently, COVID-19 Mpro has been used as a target to screen clinically approved drugs as potential inhibitors (Xu et al, 2020;Liu et al, 2020;Li et al, 2020). Since the safety profile of these FDA approved drugs is well documented and the efficacy of selected few can be quickly tested against a viral culture, the drug repurposing could be an efficient approach to find therapeutics against COVID-19.…”