scholarly journals Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1

2021 ◽  
Vol 118 (37) ◽  
pp. e2107108118
Author(s):  
Shilei Zhang ◽  
Jingfeng Wang ◽  
Genhong Cheng
Keyword(s):  
Viral Replication ◽  
Ring Finger ◽  
Prediction Method ◽  
Global Public Health ◽  
Protease Cleavage ◽  
Main Protease ◽  
Novel Host ◽  
Novel Target ◽  
Viral Polyprotein ◽  
Respiratory Coronavirus

COVID-19, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has presented a serious risk to global public health. The viral main protease Mpro (also called 3Clpro) encoded by NSP5 is an enzyme essential for viral replication. However, very few host proteins have been experimentally validated as targets of 3Clpro. Here, through bioinformatics analysis of 300 interferon stimulatory genes (ISGs) based on the prediction method NetCorona, we identify RNF20 (Ring Finger Protein 20) as a novel target of 3Clpro. We have also provided evidence that 3Clpro, but not the mutant 3ClproC145A without catalytic activity, cleaves RNF20 at a conserved Gln521 across species, which subsequently prevents SREBP1 from RNF20-mediated degradation and promotes SARS-CoV-2 replication. We show that RNA interference (RNAi)-mediated depletion of either RNF20 or RNF40 significantly enhances viral replication, indicating the antiviral role of RNF20/RNF40 complex against SARS-CoV-2. The involvement of SREBP1 in SARS-CoV-2 infection is evidenced by a decrease of viral replication in the cells with SREBP1 knockdown and inhibitor AM580. Taken together, our findings reveal RNF20 as a novel host target for SARS-CoV-2 main protease and indicate that 3Clpro inhibitors may treat COVID-19 through not only blocking viral polyprotein cleavage but also enhancing host antiviral response.

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

scholarly journals MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Vineet D. Menachery ◽  
Hugh D. Mitchell ◽  
Adam S. Cockrell ◽  
Lisa E. Gralinski ◽  
Boyd L. Yount ◽  
...  
Keyword(s):  
Public Health ◽  
Viral Replication ◽  
Rapid Response ◽  
Mutant Virus ◽  
Global Public Health ◽  
Vaccine Platform ◽  
Zoonotic Pathogens ◽  
Related Group

ABSTRACT While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.

scholarly journals Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel in Silico Method

2020 ◽  
Author(s):  
Milan Sencanski ◽  
Vladimir Perovic ◽  
Snezana Pajovic ◽  
Miroslav Adzic ◽  
Slobodan Paessler ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
In Silico ◽  
Drug Target ◽  
Transmission Rate ◽  
Experimental Testing ◽  
Drug Repurposing ◽  
Global Public Health ◽  
Main Protease ◽  
Additional Approach ◽  
Drugbank Database

<p>The SARS-CoV-2 outbreak caused an unprecedented global public health threat, having a high transmission rate with currently no drugs or vaccines approved. An alternative powerful additional approach to counteract COVID-19 is <em>in silico</em> drug repurposing. The SARS-CoV-2 main protease is essential for viral replication and an attractive drug target. In this study, we used the virtual screening (VS) protocol with both long-range and short-range interactions to select candidate SARS-CoV-2 main protease inhibitors. First, the ISM applied for Small Molecules was used for searching the Drugbank database and further followed by molecular docking. After <em>in silico</em> screening of drug space, we identified 57 drugs as potential SARS-CoV-2 main protease inhibitors that we propose for further experimental testing.</p>

scholarly journals FDA-approved thiol-reacting drugs that potentially bind into the SARS-CoV-2 main protease, essential for viral replication

2020 ◽  
pp. 1-9 ◽  
Author(s):  
Naún Lobo-Galo ◽  
Manuel Terrazas-López ◽  
Alejandro Martínez-Martínez ◽  
Ángel Gabriel Díaz-Sánchez
Keyword(s):  
Viral Replication ◽  
Main Protease

scholarly journals The Impact of the COVID-19 Pandemic on the Content and Logistics of this Special Edition on Building and Leveraging Ecosystems and Clusters

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Arthur Boni ◽  
Moira Gunn
Keyword(s):  
Media Coverage ◽  
World Health ◽  
Director General ◽  
Global Public Health ◽  
Global Media ◽  
The Media ◽  
Potential Impact ◽  
Health Organization ◽  
Respiratory Coronavirus ◽  
The Impact

On March 11, 2020, the World Health Organization (WHO) Director General Dr. Tedros Adhanom Ghebreyesus addressed the global media: “WHO has been assessing this outbreak around the clock and we are deeply concerned both by the alarming levels of spread and severity, and by the alarming levels of inaction. We have therefore made the assessment that COVID-19 can be characterized as a pandemic.”1 While the existence, transmissibility, treatment, and potential impact of severe acute respiratory coronavirus SARS-CoV-2 were real questions since the virus was first recognized in December, 2019,2 much of the media coverage was driven by global public health concerns and international/national political posturing. However, it was a different date that catalyzed commercial biotechnology.

scholarly journals Stenoparib, an Inhibitor of Cellular Poly(ADP-Ribose) Polymerase, Blocks Replication of the SARS-CoV-2 and HCoV-NL63 Human Coronaviruses In Vitro

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathan E. Stone ◽  
Sierra A. Jaramillo ◽  
Ashley N. Jones ◽  
Adam J. Vazquez ◽  
Madison Martz ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Viral Replication ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Target Range ◽  
Phase Ii Clinical Trials ◽  
Human Coronaviruses ◽  
Respiratory Coronavirus

ABSTRACT By late 2020, the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new poly(ADP-ribose) polymerase (PARP) inhibitor, stenoparib, that recently advanced to phase II clinical trials for treatment of ovarian cancer, for activity against human respiratory coronaviruses, including SARS-CoV-2, in vitro. Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to the human seasonal respiratory coronavirus HCoV-NL63. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and postentry processes, as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib—below the approximated 25.5 μM half-maximally effective concentration (EC50)—combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a stand-alone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19. IMPORTANCE New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in phase II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans have already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronaviruses in vitro. This activity appears to be based on multiple modes of action, where both pre-entry and postentry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir in combination may be especially potent against coronavirus infection.

scholarly journals Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PLpro and Mpro in in vitro studies

2020 ◽  
Author(s):  
Mikolaj Zmudzinski ◽  
Wioletta Rut ◽  
Kamila Olech ◽  
Jarosław Granda ◽  
Mirosław Giurg ◽  
...  
Keyword(s):  
Small Molecule ◽  
Antiviral Agents ◽  
Small Molecule Drug ◽  
Main Protease ◽  
Promising Target ◽  
Viral Survival ◽  
Dual Inhibitors ◽  
Viral Polyprotein ◽  
Covalent Inhibitor

AbstractProteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage - a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and anti-viral assays. In this study, we screened a collection of 23 ebselen derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Our work shows that ebselen constitutes a promising platform for development of new antiviral agents targeting both SARS-CoV-2 PLpro and Mpro.

scholarly journals Rationale Based Selection and Prioritization of Antiviral Drugs for COVID-19 Management

2020 ◽  
Author(s):  
Rakesh Joshi ◽  
Ashok P. Giri ◽  
Mahesh J. Kulkarni ◽  
mahesh gupta ◽  
Savita Verma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Drugs ◽  
Drug Combinations ◽  
Proteolytic Processing ◽  
Therapeutic Interventions ◽  
Investigational Drug ◽  
Main Protease ◽  
Specific Proteins ◽  
Viral Polyprotein ◽  
Selection Of

<div>Infection with SARS-CoV-2 has resulted in COVID-19 pandemic and infected more than 5</div><div>million individuals with around 0.35 million deaths worldwide till May 2020 end. Several</div><div>efforts are on in search of therapeutic interventions, but the preferred way is drug</div><div>repurposing due to the feasibility and urgency of the situation. To select and prioritize</div><div>approved antiviral drugs and drug combinations for COVID-19, 61 antiviral drugs having</div><div>proven safety profile in humans were subjected to virtual screening for binding to three</div><div>select targets namely human angiotensin-converting enzyme receptor-2 receptor-binding</div><div>domain (hACE-2) involved in virus entry, SARS-CoV-2 RNA dependent RNA polymerase</div><div>(RdRp) responsible for viral RNA replication and SARS-CoV-2 main protease (MPro) causing</div><div>proteolytic processing of viral polyprotein slab. Targeting multiple ‘disease pathogenesis</div><div>specific proteins’ within a close network of interaction or having dependent functionality can</div><div>provide effective intervention. Ledipasvir, Daclatasvir, Elbasvir, Paritaprevir, Rilpivirine and</div><div>Indinavir were identified as candidate drugs of interest for COVID-19 based on a derived</div><div>combined activity score, pharmacokinetic and pharmacodynamic parameters. Ledipasvir and</div><div>Daclatasvir and their approved marketed combination with Sofosbuvir emerged as leading</div><div>candidate drugs/drug combinations for SARS-CoV-2. These candidates have the potential</div><div>for the antiviral activity for SARS-CoV-2 infection better than the investigational drug</div><div>Remdesivir and other antiviral drugs/drug combinations being evaluated. These</div><div>drugs/combinations merit systematic fast track preclinical and clinical evaluation for COVID-</div><div>19 management. The present work brings back attention to the potential usefulness of</div><div>approved antiviral drugs/drug combinations, commonly available with established safety</div><div>profile, currently not in focus for COVID-19. It provides a rationale based approach for the</div><div>selection of drugs with potential antiviral activity against SARS-CoV-2 highlighting the</div><div>desired properties.</div>

scholarly journals Canthin-6-One 9-O-Beta-Glucopyranoside: an inhibitor of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro

2020 ◽  
Author(s):  
Devvret Verma ◽  
Debasis Mitra ◽  
Anshul Kamboj ◽  
Bhaswatimayee Mahakur ◽  
Priya Chaudhary ◽  
...  
Keyword(s):  
Public Health ◽  
Molecular Docking ◽  
Binding Energy ◽  
Public Health Issue ◽  
Global Public Health ◽  
Sophora Flavescens ◽  
Main Protease ◽  
Rapid Spread ◽  
Brain Barrier Permeability ◽  
Gi Absorption

Abstract The rapid spread of SARS-CoV-2 has raised a severe global public health issue, where therapy is not identified with specific drugs or vaccines. The present investigation dealt with the inhibition of various proteins and receptors of virus using phytocompounds of three pertinent medicinal plants i.e. Eurycoma harmandiana, Sophora flavescens and Andrographis paniculata. Phytocompounds known to have antiviral properties were screened against the papain-like protease (PLpro) and main protease (Mpro) / 3-chymotrypsin-like Protease (3CLpro). Molecular docking with Canthin-6-One 9-O-Beta-Glucopyranoside showed the highest binding affinity and least binding energy with both the proteases viz. PLpro and Mpro/ 3CLpro. ADMET analysis of the compound suggested that it is having drug-like properties like high gastrointestinal (gi-) absorption, no blood-brain barrier permeability, and high lipophilicity.

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