Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

Isgrò, Camilla; Sardanelli, Anna Maria; Palese, Luigi Leonardo

doi:10.3390/v13010106

Cited by 13 publications

(8 citation statements)

References 62 publications

(82 reference statements)

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“…Enzymatic assays were performed essentially as described in our previous work [65]. Briefly, we used the purified SARS-CoV-2 M pro Untagged purchased from BPS Bioscience (cat.…”

Section: In Vitro Analysesmentioning

confidence: 99%

SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

2021

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In late 2019, a global pandemic occurred. The causative agent was identified as a member of the Coronaviridae family, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we present an analysis on the substances identified in the human metabolome capable of binding the active site of the SARS-CoV-2 main protease (Mpro). The substances present in the human metabolome have both endogenous and exogenous origins. The aim of this research was to find molecules whose biochemical and toxicological profile was known that could be the starting point for the development of antiviral therapies. Our analysis revealed numerous metabolites—including xenobiotics—that bind this protease, which are essential to the lifecycle of the virus. Among these substances, silybin, a flavolignan compound and the main active component of silymarin, is particularly noteworthy. Silymarin is a standardized extract of milk thistle, Silybum marianum, and has been shown to exhibit antioxidant, hepatoprotective, antineoplastic, and antiviral activities. Our results—obtained in silico and in vitro—prove that silybin and silymarin, respectively, are able to inhibit Mpro, representing a possible food-derived natural compound that is useful as a therapeutic strategy against COVID-19.

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“…Enzymatic assays were performed essentially as described in our previous work [65]. Briefly, we used the purified SARS-CoV-2 M pro Untagged purchased from BPS Bioscience (cat.…”

Section: In Vitro Analysesmentioning

confidence: 99%

SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

2021

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“…M pro resides in nsp5 and is a key protein with proteolytic activity as the main protease. This protein is highly conserved among coronaviruses and plays an important role in mediating viral replication and transcription machinery, making it an attractive and highly specific drug target for SARS-CoV-2 25 , 26 , 27 , with little or no impact on cellular proteases [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Mahmoud

Mostafa

Al‐Karmalawy

et al. 2021

Heliyon

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Drug repurposing is an important approach to the assignment of already approved drugs for new indications. This technique bypasses some steps in the traditional drug approval system, which saves time and lives in the case of pandemics. Direct acting antivirals (DAAs) have repeatedly repurposed from treating one virus to another. In this study, 16 FDA-approved hepatitis C virus (HCV) DAA drugs were studied to explore their activities against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human and viral targets. Among the 16 HCV DAA drugs, telaprevir has shown the best in silico evidence to work on both indirect human targets (cathepsin L [CTSL] and human angiotensin-converting enzyme 2 [ h ACE2] receptor) and direct viral targets (main protease [M pro ]). Moreover, the docked poses of telaprevir inside both h ACE2 and M pro were subjected to additional molecular dynamics simulations monitored by calculating the binding free energy using MM-GBSA. In vitro analysis of telaprevir showed inhibition of SARS-CoV-2 replication in cell culture (IC 50 = 11.552 μM, CC 50 = 60.865 μM, and selectivity index = 5.27). Accordingly, based on the in silico studies and supported by the presented in vitro analysis, we suggest that telaprevir may be considered for therapeutic development against SARS-CoV-2.

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“…A dataset of compounds with reported IC 50 (half maximal inhibitory concentration) against MPro or reported residual enzyme activity at 10, 20 or 50 µM concentrations was compiled from different sources. These include 18 original articles found in the specialized literature (Akshita et al, 2020;Jin et al, 2020;Ma et al, 2020;Sacco et al, 2020;Shitrit et al, 2020;Su et al, 2020;Vuong et al, 2020;Wenhao et al, 2020;Zhang et al, 2020;Bai et al, 2021;Chun-Hui et al, 2021;Franco et al, 2021;Hattori et al, 2021;Hongbo et al, 2021;Isgrò et al, 2021;Liu et al, 2021;Mody et al, 2021;Rothan and Teoh 2021), the publicly available COVID Moonshot database (Moonshot 2021), and inhouse acquired data from our group. The literature search and data compilation from the COVID Moonshot database were performed in February 2021.…”

Section: Dataset Compilation and Curationmentioning

confidence: 99%

Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

Gori

Ruatta²,

Fló³

et al. 2023

Front. Drug. Discov.

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The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARS-CoV-2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV-2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 µM and 4 μM, respectively) but not the papain-like protease of SARS-CoV-2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARS-CoV-2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.

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Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

Cited by 13 publications

References 62 publications

SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome

Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies

Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

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