Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Macchiagodena, Marina; Pagliai, Marco; Procacci, Piero

doi:10.1016/j.cplett.2020.137489

Cited by 165 publications

(167 citation statements)

References 24 publications

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“…The potencies of LPV and LPV/RTV against CoV are from 10 to 8 μM, Glu166 is one of the residues that promotes the opeing of Mpro for its substrate to interact with the active site 36,37 .…”

Section: ) Discussionmentioning

confidence: 99%

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Fintelman-Rodrigues

Sacramento

Lima³

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019CoV disease (COVID-19) would allow the rapid implementation of potentially lifesaving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors, such as atazanavir (ATV). ATV is of high interest because of its bioavailability within the respiratory tract. Our results show that ATV could dock in the active site of SARS-CoV-2 Mpro, with greater strength than LPV.ATV blocked Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells, human pulmonary epithelial cell line and primary monocytes, impairing virus-induced enhancement of IL-6 and

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Section: ) Discussionmentioning

confidence: 99%

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Fintelman-Rodrigues

Sacramento

Lima³

et al. 2020

Preprint

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“…Structures of the protease domains of NSP3 and NSP5 have already been reported, opening the door to the identification or development of inhibitors, using virtual or high-throughput screening (e.g. [4][5][6][7][8]). Viral proteins, especially those from RNA viruses that have stricter constraints on their genome size, often perform multiple tasks.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…Usually, ß-coronaviruses yield a ~800 kDa polypeptide upon transcription of the genome. This polypeptide is proteolytically cleaved to create various proteins, and proteolytic processing is facilitated by papain-like protease, cleaving the polyprotein at 11 different spots to generate various non-structural proteins that are important for the viral reproduction [7]. Thus, this protease plays a key role in the duplication of virus particles, and unlike structural/accessory protein-encoding genes located at the 3' end that exhibit extreme variability, it may assist as a possible target for anti-COVID-19 inhibitors [8].…”

Section: Introductionmentioning

confidence: 99%

Anti-COVID-19 Effects of Ten Structurally Different Hydrolysable Tannins through Binding with the Catalytic-Closed Sites of COVID-19 Main Protease: An In-Silico Approach

Khalifa¹,

Zhu²,

Ms³

et al. 2020

Preprint

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Coronavirus disease 2019 (COVID-19) was recently raised and starting from China to all over the world. The viral main protease (3-chymotrypsin-like cysteine enzyme) controls COVID-19 duplication and manages its life cycle, making it a drug discovery target. Therefore, herein, we analyzed the theoretical approaches of 10 structurally different hydrolysable tannins as natural anti-COVID-19 through binding with the main protease of 2019-nCoV using molecular docking modelling via Molecular Operating Environment (MOE v2009) software. Our results revealed that there are top three hits may serve as potential anti-COVID-19 lead molecules for further optimization and drug development to control COVID-19. Pedunculagin, tercatain, and punicalin were found to faithfully interact with the receptor binding site and catalytic dyad (Cys145 and His41) of COVID-19 main protease, showing their successfully inhibit the protease enzyme of 2019-nCoV. We anticipated that this study would pave way for tannins based novel small molecules as more efficacious and selective anti-COVID-19 therapeutic compounds.

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Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling

Cited by 165 publications

References 24 publications

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Anti-COVID-19 Effects of Ten Structurally Different Hydrolysable Tannins through Binding with the Catalytic-Closed Sites of COVID-19 Main Protease: An In-Silico Approach

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