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    Disulfiram associated with lower risk of Covid-19 MESHD: a retrospective cohort study

    Authors: Nathanael Fillmore; Steven Bell; Ciyue Shen; Vinh Nguyen; Jennifer La; Maureen Dubreuil; Judith Strymish; Mary Brophy; Gautam Mehta; Hao Wu; Judy Lieberman; Nhan Do; Chris Sander

    doi:10.1101/2021.03.10.21253331 Date: 2021-03-12 Source: medRxiv

    In the global COVID-19 pandemic MESHD, there is a substantial need for effective, low-cost therapeutics. We investigated the potential effects of disulfiram on the incidence and outcomes of COVID-19 MESHD in an observational study in a large database of US Veterans Administration clinical records, the VA Corporate Data Warehouse (CDW). The study is motivated by the unique properties of disulfiram, which has been used as an anti-alcoholism drug since 1948, is non-toxic, easy to manufacture and inexpensive. Disulfiram reduces hyperinflammation in mammalian cells by inhibition of the gasdermin D HGNC pore. In a mouse model of sepsis MESHD, disulfiram reduced inflammatory cytokines and mortality. Disulfiram also is a low micromolar inhibitor of the Mpro PROTEIN and PLpro PROTEIN viral proteases of SARS-CoV-2. To investigate the potential effects of disulfiram on the incidence and severity of COVID-19 MESHD, we carried out an epidemiological study in the CDW. The VA dataset used has 944,127 patients tested for SARS-Cov-2, 167,327 with a positive test, and 2,233 on disulfiram, of which 188 had a positive SARS-Cov-2 test. A multivariable Cox regression adjusted for age, gender, race/ethnicity, region, a diagnosis of alcohol use disorders, and Charlson comorbidity score revealed a reduced incidence of COVID-19 MESHD with disulfiram use with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). There were no deaths among the 188 SARS-Cov-2 positive patients treated with disulfiram. The expected number of deaths would have been 5-6 according to the 3% death rate among the untreated (P-value 0.03). Our finding of a lower hazard ratio and less severe outcomes for COVID-19 MESHD in patients treated with disulfiram compared to those not treated is a statistical association and does not prove any causative effect of disulfiram. However, the results of this study suggest that there is a pharmacological contribution to the reduced incidence and severity of COVID-19 MESHD with the use of disulfiram. Given the known anti-inflammatory and viral anti-protease effects of disulfiram, it is reasonable and urgent to initiate accelerated clinical trials to assess whether disulfiram reduces SARS-CoV-2 infection MESHD, disease severity and death MESHD.

    High-content screening of coronavirus genes for innate immune suppression revealsenhanced potency of SARS-CoV-2 proteins

    Authors: Erika J Olson; David M Brown; Timothy Z Chang; Lin Ding; Tai L Ng; H. Sloane Weiss; Peter Koch; Yukiye Koide; Nathan Rollins; Pia Mach; Tobias Meisinger; Trenton Bricken; Joshus Rollins; Yun Zhang; Colin Molloy; Yun Zhang; Briodget N Queenan; Timothy Mitchison; Debora Marks; Jeffrey C Way; John I Glass; Pamela A Silver

    doi:10.1101/2021.03.02.433434 Date: 2021-03-02 Source: bioRxiv

    Suppression of the host intracellular innate immune system is an essential aspect of viral replication. Here, we developed a suite of medium-throughput high-content cell-based assays to reveal the effect of individual coronavirus proteins on antiviral innate immune pathways. Using these assays, we screened the 196 protein products of seven coronaviruses (SARS-CoV-2,SARS-CoV-1, 229E, NL63, OC43, HKU1 and MERS). This includes a previously unidentified gene in SARS-CoV-2 encoded within the Spike gene. We observe immune-suppressing activity in both known host-suppressing genes (e PROTEIN.g., NSP1, Orf6, NSP3 PROTEIN, and NSP5 PROTEIN) as well as other coronavirus genes, including the newly identified SARS-CoV-2 protein. Moreover, the genes encoded by SARS-CoV-2 are generally more potent immune suppressors than their homologues from the other coronaviruses. This suite of pathway-based and mechanism-agnostic assays could serve as the basis for rapid in vitro prediction of the pathogenicity of novel viruses based on provision of sequence information alone.

    Active constituents and Molecular Analysis of Psidium guajava Against Multiple Protein of SARS-CoV-2

    Authors: Fadilah Fadilah; Linda Erlina; Rafika Indah Paramita; Khaerunissa Anbar Istiadi; Raden Rara Diah Handayani

    doi:10.21203/rs.3.rs-271919/v1 Date: 2021-02-23 Source: ResearchSquare

    Background The severe acute respiratory syndrome MESHD COVID-19 MESHD declared as a global pandemic by the World Health Organization has become the present wellbeing worry to the whole world. The latest development of COVID-19 MESHD spread in Indonesia has reached 1.024.298 cases, with 28.855 patients died, updated on January 28, 2021. Unfortunately, these numbers continue to overgrow, and no drug has yet been approved for effective treatment. There is an emergent need to search for possible medications and explore the potential of Indonesian herbal compounds. Ministry of Health Indonesia stated that Psidium guajava can be use as daily nutritional supplement during COVID-19 pandemic MESHD. This study aims to determine the potential active constituents in Psidium guajava as an inhibitor for multiple SARS-CoV-2 proteins using molecular analysis.Methods Molecular docking was performed by using Autodocktools 1.5.6. We performed a structure-based virtual screening of fourteen 3D structure of Psidium guajava compounds, three antivirals (lopinavir, remdesivir, and ritonavir) against multiple SARS-CoV-2 proteins. We download the main protease PROTEIN (3CLPro), Papain Like Protease PROTEIN (PL Pro), MPro, Spike and ACE2 HGNC as protein target from human against from Protein Data Bank (PDB). We used PyMOL to analyse the interactions between the SARS-CoV-2 proteins and 14 compounds from Psidium guajava and three antiviral (lopinavir, remdesivir and ritonavir) used as positive control.Results Based on the molecular docking analysis, it was found there are two potential compounds that showed higher binding affinity score namely gamma sitosterol and peri-xanthenoxanthene-4,10-dione,2,8-bis (1-methylethyl).Conclusions Gamma sitosterol and peri-xanthenoxanthene-4,10-dione,2,8-bis (1-methylethyl) from Psidium guajava have potential as antiviral candidates for SARS-CoV-2 multiple proteins such as main protease PROTEIN (3CLPro), Papain Like Protease PROTEIN (PL Pro), MPro, Spike and ACE2 HGNC.

    Potent, Novel SARS-CoV-2 PLpro PROTEIN Inhibitors Block Viral Replication in Monkey and Human Cell Cultures

    Authors: Zhengnan Shen; Kiira Ratia; Laura Cooper; Deyu Kong; Hyun Lee; Youngjin Kwon; Yangfeng Li; Saad Alqarni; Fei Huang; Oleksii Dubrovskyi; Lijun Rong; Gregory RJ Thatcher; RUI XIONG

    doi:10.1101/2021.02.13.431008 Date: 2021-02-15 Source: bioRxiv

    Antiviral agents blocking SARS-CoV-2 viral replication are desperately needed to complement vaccination to end the COVID-19 pandemic MESHD. Viral replication and assembly are entirely dependent on two viral cysteine proteases: 3C-like protease ( 3CLpro PROTEIN) and the papain-like protease PROTEIN ( PLpro PROTEIN). PLpro PROTEIN also has deubiquitinase (DUB) activity, removing ubiquitin (Ub) and Ub-like modifications from host proteins, disrupting the host immune response. 3CLpro PROTEIN is inhibited by many known cysteine protease inhibitors, whereas PLpro PROTEIN is a relatively unusual cysteine protease, being resistant to blockade by such inhibitors. A high-throughput screen of biased and unbiased libraries gave a low hit rate, identifying only CPI-169 and the positive control, GRL0617, as inhibitors with good potency (IC50 < 10 lower case Greek M). Analogues of both inhibitors were designed to develop structure-activity relationships; however, without a co-crystal structure of the CPI-169 series, we focused on GRL0617 as a starting point for structure-based drug design, obtaining several co-crystal structures to guide optimization. A series of novel 2-phenylthiophene-based non-covalent SARS-CoV-2 PLpro PROTEIN inhibitors were obtained, culminating in low nanomolar potency. The high potency and slow inhibitor off-rate were rationalized by newly identified ligand interactions with a ' BL2 HGNC groove' that is distal from the active site cysteine. Trapping of the conformationally flexible BL2 HGNC loop by these inhibitors blocks binding of viral and host protein substrates; however, until now it has not been demonstrated that this mechanism can induce potent and efficacious antiviral activity. In this study, we report that novel PLpro PROTEIN inhibitors have excellent antiviral efficacy and potency against infectious SARS-CoV-2 replication in cell cultures. Together, our data provide structural insights into the design of potent PLpro PROTEIN inhibitors and the first validation that non-covalent inhibitors of SARS-CoV-2 PLpro PROTEIN can block infection of human cells with low micromolar potency.

    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.

    Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

    Authors: Anneliese Ashhurst; Arthur Tang; Pavla Fajtova; Michael Yoon; Anupriya Aggarwal; Alexander Stoye; Mark Larance; Laura Beretta; Aleksandra Drelich; Danielle Skinner; Linfeng Li; Thomas Meek; James McKerrow; Vivian Hook; Chien-Te Tseng; Stuart Grant Turville; William Gerwick; Richard J Payne; Myra Hosmillo; Malte L Pinckert; Iliana Georgana; Anna Yakovleva; Laura G Caller; Sarah L Caddy; Theresa Feltwell; Fahad A Khokhar; Charlotte J Houldcroft; Martin D Curran; Surendra Parmar; - The COVID-19 Genomics UK (COG-UK) Consortium; Alex Alderton; Rachel Nelson; Ewan Harrison; John Sillitoe; Stephen D Bentley; Jeffrey C Barrett; M. Estee Torok; Ian G Goodfellow; Cordelia Langford; Dominic Kwiatkowski; - Wellcome Sanger Institute COVID-19 Surveillance Team

    doi:10.1101/2020.12.23.424111 Date: 2020-12-25 Source: bioRxiv

    The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic MESHD COVID-19 pandemic MESHD, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L HGNC is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L HGNC activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B HGNC and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro PROTEIN and PLpro PROTEIN. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection MESHD in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L HGNC as a COVID-19 MESHD antiviral drug target.

    Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture

    Authors: Khushboo Bafna; Kris White; Balasubramanian Harish; Romel Rosales; Theresa A Ramelot; Thomas B. Acton; Elena Moreno; Thomas Kehrer; Catherine A. Royer; Adolfo Garcia-Sastre; Robert M Krug; Gaetano T. Montelione

    doi:10.1101/2020.12.13.422511 Date: 2020-12-14 Source: bioRxiv

    Effective control of COVID-19 MESHD requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mpro PROTEIN and HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mpro PROTEIN binding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mpro PROTEIN protease activity, while four dock well into the PLpro PROTEIN substrate binding cleft MESHD and inhibit PLpro PROTEIN protease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit Mpro PROTEIN, or both Mpro PROTEIN and PLpro PROTEIN, suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold. HighlightsO_LISeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mpro PROTEIN and PLpro PROTEIN. C_LIO_LISeven HCV drugs inhibit Mpro PROTEIN enzyme activity, four HCV drugs inhibit PLpro PROTEIN. C_LIO_LISeven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells. C_LIO_LIHCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2. C_ LI eTOC blurbBafna MESHD, White and colleagues report that several available hepatitis C MESHD virus drugs inhibit the SARS-CoV-2 Mpro PROTEIN and/or PLpro PROTEIN proteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/422511v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@d21075org.highwire.dtl.DTLVardef@13678edorg.highwire.dtl.DTLVardef@13d103aorg.highwire.dtl.DTLVardef@1f45fdb_HPS_FORMAT_FIGEXP M_FIG C_FIG

    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.

    Naturally occurring phytochemical as inhibitors from Catharanthus roseus: An In-silico approaches for drug development against COVID-19 MESHD

    Authors: Rishee K. Kalaria; Hiren K. Patel

    doi:10.21203/rs.3.rs-116443/v1 Date: 2020-11-26 Source: ResearchSquare

    The current outbreak of the novel 2019 Coronavirus disease MESHD ( COVID-19 MESHD) is caused by SARS-CoV-2, has developed a threat to the world's human population. There are no effective therapies or vaccines yet, urging the serious efforts to tackle this pandemic situation. SARS-CoV-2 spike PROTEIN protein, papain like protease PROTEIN protein (PLPRO), main protease PROTEIN ( 3CLpro PROTEIN) and RNA dependent DNA polymerase are key factors in the virus infectious process and have been identified as potential targets for therapeutic formulation. Most people in India depend on conventional Indian medicine (phytochemical compounds) to treat diseases MESHD due to lower cost, easier accessibility and no adverse effects. A lot of studies have recently shown that phytochemicals contain an effective anti-viral activity. This study aims to investigate phytochemicals metabolites from the IMPPAT database (Indian Medicinal Plants Database) in order to identify potential COVID-19 MESHD inhibitors using in silico approaches. Certain phytochemical compounds with structure analogs like hydroxychloroquine and chloroquine from the IMPPAT database were taken for interaction with SARS-CoV-2 proteins MESHD. The Apparicine, 12-Chlorotabersonine, AC1NSULH and Vindolininol identified from Catharanthus roseus were further checked the ADMET property as well as ‘Lipinski’s rule and resulted in a strong binding affinity of (-7.6,-7.5) and (-7.6 -7.5) kcal/mol respectively for spikes and papain like protease PROTEIN protein of SARS-CoV-2. Our results indicate that these specific compounds can be used as effective inhibitors and help to pace up the drug development against SARS-CoV-2. Further investigation and testing of these inhibitors against SARS‐CoV‐2 are however required to check their clinical trial candidacy.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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