Repurposing an Antiviral Drug against SARS‐CoV‐2 Main Protease

Sarkar, Arighna; Mandal, Kalyaneswar

doi:10.1002/anie.202107481

Cited by 25 publications

(15 citation statements)

References 18 publications

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“…Extensive research has revealed that the SARS-CoV-2 main protease (M pro , also called 3C-like protease) plays an essential role in the polyprotein maturation process, offering a relevant therapeutic target that is influenced by anti-SARS-CoV-2 prodrug treatment. 33,51,52 2.1 | PF-07304814 PF-07304814, a highly selective M pro inhibitor developed by Pfizer Inc., is a novel phosphate prodrug that is metabolized intracellularly to the active form, PF-00835231; it was initially identified during 2002-2003 for the treatment of SARS-CoV and has demonstrated broad-spectrum antiviral activity in vitro and in vivo. 53 PF-00835231 exhibits strong anti-SARS-CoV-2 activity in Vero E6 cells with a halfmaximal effective concentration (EC 50 ) value of 0.23 µM without significant cytotoxicity.…”

Section: Broad-spectrum Prodrugs Targeting the Sars-cov-main Proteasementioning

confidence: 99%

Broad‐spectrum prodrugs with anti‐SARS‐CoV‐2 activities: Strategies, benefits, and challenges

Wang

Yang

2021

Journal of Medical Virology

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In this era, broad‐spectrum prodrugs with anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) activities are gaining considerable attention owing to their potential clinical benefits and role in combating the fast‐spreading coronavirus disease 2019 (COVID‐19) pandemic. The last 2 years have seen a surge of reports on various broad‐spectrum prodrugs against SARS‐CoV‐2, and in in vitro studies, animal models, and clinical practice. Currently, only remdesivir (with many controversies and limitations) has been approved by the U.S. FDA for the treatment of SARS‐CoV‐2 infection, and additional potent anti‐SARS‐CoV‐2 drugs are urgently required to enrich the defense arsenals. The world has ubiquitously grappled with the COVID‐19 pandemic, and the availability of broad‐spectrum prodrugs provides great hope for us to subdue this global threat. This article reviews promising treatment strategies, antiviral mechanisms, potential benefits, and daunting clinical challenges of anti‐SARS‐CoV‐2 agents to provide some important guidance for future clinical treatment.

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Section: Broad-spectrum Prodrugs Targeting the Sars-cov-main Proteasementioning

confidence: 99%

Broad‐spectrum prodrugs with anti‐SARS‐CoV‐2 activities: Strategies, benefits, and challenges

Wang

Yang

2021

Journal of Medical Virology

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“…The currently approved drugs for treating the infected patients show limited and toxic side effects. Thus, more effective antiviral drugs are still urgently desired [ 1 , 2 , 3 ]. The SARS-CoV-2 main protease (Mpro), also known as 3C-like protease (3CLpro), is involved in cleaving the viral polyprotein to produce the essential viral protein required for virus replication and pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Colorimetric and Electrochemical Methods for the Detection of SARS-CoV-2 Main Protease by Peptide-Triggered Assembly of Gold Nanoparticles

Feng

Liu

et al. 2022

Molecules

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) has been regarded as one of the ideal targets for the development of antiviral drugs. The currently used methods for the probing of Mpro activity and the screening of its inhibitors require the use of a double-labeled peptide substrate. In this work, we suggested that the label-free peptide substrate could induce the aggregation of AuNPs through the electrostatic interactions, and the cleavage of the peptide by the Mpro inhibited the aggregation of AuNPs. This fact allowed for the visual analysis of Mpro activity by observing the color change of the AuNPs suspension. Furthermore, the co-assembly of AuNPs and peptide was achieved on the peptide-covered electrode surface. Cleavage of the peptide substrate by the Mpro limited the formation of AuNPs/peptide assembles, thus allowing for the development of a simple and sensitive electrochemical method for Mpro detection in serum samples. The change of the electrochemical signal was easily monitored by electrochemical impedance spectroscopy (EIS). The detection limits of the colorimetric and electrochemical methods are 10 and 0.1 pM, respectively. This work should be valuable for the development of effective antiviral drugs and the design of novel optical and electrical biosensors.

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“…Due to the immediate availability of the M pro crystal structure, structure-based drug discovery (SBDD) techniques were promptly used to expedite the rational identification of potential M pro inhibitors [ 5 , 6 , 7 ] or to drive the repurposing of known molecules [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Many protease inhibitors of the human immunodeficiency virus (HIV) were identified as possible anti-COVID candidates [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

et al. 2022

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The persistency of COVID-19 in the world and the continuous rise of its variants demand new treatments to complement vaccines. Computational chemistry can assist in the identification of moieties able to lead to new drugs to fight the disease. Fullerenes and carbon nanomaterials can interact with proteins and are considered promising antiviral agents. Here, we propose the possibility to repurpose fullerenes to clog the active site of the SARS-CoV-2 protease, Mpro. Through the use of docking, molecular dynamics, and energy decomposition techniques, it is shown that C60 has a substantial binding energy to the main protease of the SARS-CoV-2 virus, Mpro, higher than masitinib, a known inhibitor of the protein. Furthermore, we suggest the use of C70 as an innovative scaffold for the inhibition of SARS-CoV-2 Mpro. At odds with masitinib, both C60 and C70 interact more strongly with SARS-CoV-2 Mpro when different protonation states of the catalytic dyad are considered. The binding of fullerenes to Mpro is due to shape complementarity, i.e., vdW interactions, and is aspecific. As such, it is not sensitive to mutations that can eliminate or invert the charges of the amino acids composing the binding pocket. Fullerenic cages should therefore be more effective against the SARS-CoV-2 virus than the available inhibitors such as masinitib, where the electrostatic term plays a crucial role in the binding.

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Repurposing an Antiviral Drug against SARS‐CoV‐2 Main Protease

Cited by 25 publications

References 18 publications

Broad‐spectrum prodrugs with anti‐SARS‐CoV‐2 activities: Strategies, benefits, and challenges

Broad‐spectrum prodrugs with anti‐SARS‐CoV‐2 activities: Strategies, benefits, and challenges

Colorimetric and Electrochemical Methods for the Detection of SARS-CoV-2 Main Protease by Peptide-Triggered Assembly of Gold Nanoparticles

Fullerenes against COVID-19: Repurposing C60 and C70 to Clog the Active Site of SARS-CoV-2 Protease

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