Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection

Abstract

The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti–SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.

Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

“…This finding affords a further validation of the overall predictive power of the reported VS strategies, especially considering that the inhibition activity of several SARS-CoV 3CL-Pro inhibitors against the SARS-CoV-2 3CL-Pro enzyme was experimentally confirmed (as discussed above for TG-0205221 analogues. Among the other 102 molecules, there are 37 compounds that are known inhibitors of SARS-CoV 3CL-Pro but with pIC50 < 5, and 17 known inhibitors of the main proteases of other viruses (such as norovirus and HIV), and these compounds represent a further confirmation of the efficacy of the performed VS campaigns, since some of the retrieved hits (rupintrivir [31], saquinavir [32], and lopinavir [33]) were experimentally confirmed as promising inhibitors of SARS-CoV-2 3CL-Pro. Finally, among the other common molecules, cobicistat [34] and galloyl analogues [35] were identified as SARS-CoV-2 3CL-Pro inhibitors.…”

“…Notably, the analysis of the LiGen results also comprised the pharmacophoric distances as computed by this tool. The consensus analyses were performed by the EFO approach, which generates linear combinations of score values by exhaustively combining all possible variables and by optimizing a quality function based on both the early recognition (as encoded by the corresponding EF 1% values) and the entire ranking (as encoded by an asymmetry index applied to the distribution of the active molecules) [33].…”

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer

“…Nelfinavir (Viracept), the first HIV-1 protease inhibitor developed by Agouron Pharmaceuticals, was approved by the FDA in March 1997 for the treatment of HIV-AIDS [ 138 ]. Recently, nelfinavir was shown to be effective at inhibiting SARS-CoV-2 M pro infection (IC 50 = 3.3 μM) with a low level of toxicity (SI = 3.7) [ 139 ]. In addition, nelfinavir inhibited SARS-CoV-2 replication in vitro with an EC 50 of 1.13 μM [ 140 ].…”

Molecular Basis for Reduced Cleavage Activity and Drug Resistance in D30N HIV-1 protease

“…Nelfinavir mesylate, Viracept is one of the FDA approved HIV protease inhibitors developed by Agouron Pharmaceuticals using structure based drug design strategy and Monte Carlo simulations [Gehlhaar et al 1995]. Recently, nelfinavir is also shown to be effective against Covid-19 as it inhibits SARS-CoV-2 3CL protease (Jan et al, 2021). Nelfinavir has also shown anti-cancer properties through its effects on different cellular conditions like cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps (Subeha and Telleria, 2020).…”