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    Synergistic Inhibition of SARS-CoV-2 Replication using Disulfiram/Ebselen and Remdesivir

    Authors: Ting Chen; Cheng-Yin Fei; Yi-Ping Chen; Karen Sargsyan; Chun Ping Chang; Hanna S. Yuan; Carmay Lim

    doi:10.26434/chemrxiv.13604015.v2 Date: 2021-03-11 Source: ChemRxiv

    The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2-16 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and in evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease PROTEIN or the RNA-dependent RNA polymerase PROTEIN. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance and/or evasion of antiviral drugs. We show that clinically-safe Zn-ejector drugs, disulfiram/ebselen, can target conserved Zn2+-sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease PROTEIN activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram/ebselen, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multi-targeting strategy, which can be applied to any type of coronavirus with conserved Zn2+-sites.

    Atorvastatin effectively inhibits late replicative cycle steps of SARS-CoV-2 in vitro

    Authors: Maria Isabel Zapata-Cardona; Lizdany Flórez-Álvarez; Wildeman Zapata-Builes; Ariadna Guerra-Sandoval; Carlos Guerra-Almonacid; Jaime Hincapié-García; Maria Teresa Rugeles; Juan Carlos Hernández

    doi:10.1101/2021.03.01.433498 Date: 2021-03-03 Source: bioRxiv

    Introduction: SARS-CoV-2 has caused a pandemic of historic proportions and continues to spread worldwide. Currently, there is no effective therapy against this virus. This article evaluated the in vitro antiviral effect of Atorvastatin against SARS-CoV-2 and also identified the interaction affinity between Atorvastatin and three SARS-CoV-2 proteins MESHD, using in silico structure-based molecular docking approach. Materials and methods: The antiviral activity of Atorvastatin against SARS-CoV-2 was evaluated by three different treatment strategies using a clinical isolate of SARS-CoV-2. The interaction of Atorvastatin with Spike, RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) and 3C-like protease ( 3CLpro PROTEIN) was evaluated by molecular docking. Results: Atorvastatin showed anti-SARS-CoV-2 activity of 79%, 54.8%, 22.6% and 25% at 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by pre-post-treatment strategy. In addition, atorvastatin demonstrated an antiviral effect of 26.9% at 31.2 {micro}M by pre-infection treatment. This compound also inhibited SARS-CoV-2 in 66.9%, 75%, 27.9% and 29.2% at concentrations of 31.2, 15.6, 7.9, and 3.9 {micro}M, respectively, by post-infection treatment. The interaction of atorvastatin with SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD, RdRp PROTEIN and 3CL protease PROTEIN yielded a binding affinity of -8.5 Kcal/mol, -6.2 Kcal/mol, and -7.5 Kcal/mol, respectively. Conclusion: Our study demonstrated the in vitro anti-SARS-CoV-2 activity of Atorvastatin, mainly against the late steps of the viral replicative cycle. A favorable binding affinity with viral proteins by bioinformatics methods was also shown. Due to its low cost, availability, well-established safety and tolerability, and the extensive clinical experience of atorvastatin, it could prove valuable in reducing morbidity and mortality from COVID-19 MESHD.

    The impact of mutations on the structural and functional properties of SARS-CoV-2 proteins: A comprehensive bioinformatics analysis

    Authors: Aqsa Ikram; Anam Naz; Faryal Awan; Bisma Rauff; Ayesha Obaid; Mohamad S. Hakim; Arif Malik

    doi:10.1101/2021.03.01.433340 Date: 2021-03-01 Source: bioRxiv

    An in-depth analysis of first wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness MESHD. In the present study, we have performed comprehensive in-silico mutational analysis of 3C-like protease ( 3CLpro PROTEIN), RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), and spike (S) proteins PROTEIN with the aim of gaining important insights into first wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 3465 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp PROTEIN, and 11 in 3CLpro PROTEIN regions. The impact of those mutations was also investigated using various in silico approaches. Among these 32 mutations in S, 15 in RdRp PROTEIN, and 3 in 3CLpro PROTEIN proteins are found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. D614G mutation in spike and P323L in RdRp PROTEIN are the globally dominant variants with a high frequency. Most of them have also been found in the binding moiety of the viral proteins which determine their critical involvement in the host-pathogen interactions and drug targets. The findings of the current study may facilitate better understanding of COVID-19 MESHD diagnostics, vaccines, and therapeutics.

    DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins MESHD

    Authors: Sarah Hall-Swan; Dinler A Antunes; Didier Devaurs; Mauricio M Rigo; Lydia E Kavraki; Geancarlo Zanatta; Mohit Kumar Divakar; Panyam Suresh; Disha Sharma; Nambi Rajesh; Rahul C Bhoyar; Dasari Ankaiah; Sanaga Shanthi Kumari; Gyan Ranjan; Valluri Anitha Lavanya; Mercy Rophina; S. Umadevi; Paras Sehgal; Avula Renuka Devi; A. Surekha; Pulala Chandra; Rajamadugu Hymavathy; P R Vanaja; Vinod Scaria; Sridhar Sivasubbu; Chloe Simela; Veronica French; Rachel Harris; Sharon A.M. Stevelink; Simon Wessely

    doi:10.1101/2021.01.21.427315 Date: 2021-01-22 Source: bioRxiv

    Motivation: Recent efforts to computationally identify inhibitors for SARS-CoV-2 proteins have largely ignored the issue of receptor flexibility. We have implemented a computational tool for ensemble docking with the SARS-CoV-2 proteins, including the main protease PROTEIN ( Mpro PROTEIN), papain-like protease PROTEIN ( PLpro PROTEIN) and RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN). Results: Ensembles of other SARS-CoV-2 proteins are being prepared and made available through a user-friendly docking interface. Plausible binding modes between conformations of a selected ensemble and an uploaded ligand are generated by DINC, our parallelized meta-docking tool. Binding modes are scored with three scoring functions, and account for the flexibility of both the ligand and receptor. Additional details on our methods are provided in the supplementary material. Availability: dinc-covid.kavrakilab.org . Supplementary information: Details on methods for ensemble generation and docking are provided as supplementary data online.

    Unravelling Vitamins as Wonder Molecules for Covid-19 MESHD Management via Structure-based Virtual Screening

    Authors: Medha Pandya; Sejal Shah; Dhanalakshmi Menamadathil; Ayushman Gadnayak; Tanzil Juneja; Amisha Patel; Kajari Das; Jayashankar Das

    doi:10.21203/rs.3.rs-144177/v1 Date: 2021-01-09 Source: ResearchSquare

    The emergence situation of coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic has realised the global scientific communities to develop strategies for immediate priorities and long-term approaches for utilization of existing knowledge and resources which can be diverted to pandemic preparedness planning. Lack of proper vaccine candidate and therapeutic management has accelerated the researchers to repurpose the existing drugs with known preclinical and toxicity MESHD profiles, which can easily enter Phase 3 or 4 or can be used directly in clinical settings. We focused to justify even exploration of supplements, nutrients and vitamins to dampen the disease burden of the current pandemic may play a crucial role for its management. We have explored structure based virtual screening of 15 vitamins against non-structural ( NSP3 HGNC NSP3 PROTEIN, NSP5 PROTEIN NSP5 HGNC, ORF7a PROTEIN, NSP12 PROTEIN, ORF3a PROTEIN), structural (Spike & Hemagglutinin esterase) and host protein furin HGNC. The in silico analysis exhibited that vitamin B12, Vitamin B9, Vitamin D3 determined suitable binding while vitamin B15 manifested remarkable H-bond interactions with all targets. Vitamin B12 bestowed the lowest energies with human furin HGNC and SARS-COV-2 RNA dependent RNA polymerase PROTEIN. Furin HGNC mediated cleavage of the viral spike glycoprotein PROTEIN is directly related to enhanced virulence of SARS-CoV-2. In contrast to these, vitamin B12 showed zero affinity with SARS-CoV-2 spike PROTEIN protein. These upshots intimate that Vitamin B12 could be the wonder molecule to shrink the virulence by hindering the furin HGNC mediated entry of spike to host cell. These identified molecules may effectively assist in SARS-CoV-2 therapeutic management to boost the immunity by inhibiting the virus imparting relief in lung inflammation MESHD.

    Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV- 2 non-structural proteins PROTEIN

    Authors: Igors Dubanevics; Charles Heaton; Carlos Riechmann; Tom C B McLeish; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.12.422477 Date: 2020-12-14 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic MESHD, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro PROTEIN ( nsp5 HGNC) to three other SARS-CoV-2 proteins: host shutoff factor PROTEIN ( nsp1 HGNC), papain-like protease PROTEIN ( nsp3 HGNC, also known as PLpro PROTEIN) and RNA-dependent RNA-polymerase PROTEIN (nsp12, also known as RdRp) in complex PROTEIN with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

    Tea flavonoids blocking multiple SARS-CoV-2 protein targets judged from molecular docking

    Authors: Lufei Wang; Siyao Sang; Mingjie Su; Simin Wang; Hui Li

    doi:10.21203/rs.3.rs-122589/v1 Date: 2020-12-05 Source: ResearchSquare

    Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) has caused Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) pandemic. Flavonoids derived Chinese patent medicines has outstanding curative effects for the improvement and treatment of COVID-19 MESHD. There are numerous studies suggesting that flavonoids-rich tea have antiviral effects. However, bioactive compounds from tea flavonoids with anti- COVID-19 MESHD effect, and the potential molecular mechanisms are unclear. In this study, we performed a molecular docking of 468 tea flavonoids and its derivatives with main protease PROTEIN ( Mpro PROTEIN), angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC), RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN), compared with the positive control drugs of each target. The results suggested that ACE2 HGNC and RdRp PROTEIN are the main targets inhibited by tea flavonoids.Q3G Isovitexin, and TF would be considered as the potential candidate compounds of RdRp PROTEIN and ACE2 HGNC. Our study provides a theoretical basis for further drug design of anti- COVID-19 MESHD.

    In Vitro: Natural Compounds (Thymol, Carvacrol, Hesperidine, And Thymoquinone) Against Sars-Cov2 Strain Isolated From Egyptian Patients

    Authors: Mohamed G Seadawy; Ahmed F. Gad; Mohamed Shamel; Bassem Elharty; Mostfa F. Mohamed; Abdo A. Elfiky; Aya Ahmed; Abdel Rahman N. Zekri

    doi:10.21203/rs.3.rs-119568/v1 Date: 2020-12-01 Source: ResearchSquare

    Background: The current pandemic of the coronavirus disease-2019 ( COVID-19 MESHD) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus MESHD ( HCV MESHD) and Human Immunodeficiency Virus (HIV) MESHD. Methods: Molecular docking combined with cytotoxicity MESHD and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp PROTEIN, and Mpro PROTEIN) and host-cell (TMPRSS II, keap 1 HGNC, and ACE2 HGNC) targets. Results: The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease PROTEIN ( Mpro PROTEIN). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)Conclusion: Development of an effective anti-viral for SARS-CoV-2  could help to limit the viral load. Benchmarking testing of those natural compounds against other potential antivirals for SARS-CoV-2 with alternative mechanisms of action would thus be important as soon as practicable.

    The Preclinical Inhibitor GS441524 in Combination with GC376 Efficaciously Inhibited the Proliferation of SARS-CoV-2 in the Mouse Respiratory Tract

    Authors: Yuejun Shi; Lei Shuai; Chong Wang; Yuanyuan Yan; Zhe Jiao; Fenglin Guo; Zhen F. Fu; Huanchun Chen; Zhi-Gao Bu; Guiqing Peng; Marnix Van Loock; Leo James; Jakob luptak; Guinevere L Grice; Soraya Ebrahimi; Xiaoli Xiong; John AG Briggs; Sumita Pai; angalee nadesalingham; Marie-Christine Ouellet; Marc-André Roy; Marie-Christine Saint-Jacques; Claudia Savard

    doi:10.1101/2020.11.12.380931 Date: 2020-11-13 Source: bioRxiv

    The unprecedented coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase PROTEIN enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease PROTEIN, using a mouse-adapted SARS-CoV-2 infected MESHD mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection MESHD via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.

    Approach Towards Drugs Repurposing: Docking Studies with Multiple Target Proteins Associated with SARS-CoV-2

    Authors: Shiwani Rana; Meghali Panwar; Kalyan Sundar Ghosh

    doi:10.26434/chemrxiv.12469172.v2 Date: 2020-11-09 Source: ChemRxiv

    The current pandemic outbreak of COVID-19 MESHD due to viral infections MESHD by SARS-CoV-2 is now become associated with severe commotion on global healthcare and economy. In this extreme situation when vaccine or drugs against COVID-19 MESHD are not available, the only quick and feasible therapeutic alternative would be the drug repurposing approach. In the present work, in silico screening of some antiviral and antiprotozoal drugs using Autodock docking tool was performed. Two known antiviral drugs sorivudine and noricumazole B are predicted to bind to the active site of the viral proteases namely cysteine like protease PROTEIN or 3CL protease PROTEIN ( 3CLpro PROTEIN) and papain like protease PROTEIN ( PLpro PROTEIN) respectively with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets like spike protein S1 PROTEIN, RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN) and angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) receptor. But the compounds were found not effective on rest other molecular targets.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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