Corpus overview


Overview

MeSH Disease

Human Phenotype

Transmission

Seroprevalence
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    A drug repurposing screen identifies hepatitis C MESHD hepatitis HP antivirals as inhibitors of the SARS-CoV-2 main protease.

    Authors: Jeremy D Baker; Rikki L Uhrich; Gerald C Kraemer; Jason E Love; Brian C Kraemer

    doi:10.1101/2020.07.10.197889 Date: 2020-07-10 Source: bioRxiv

    The SARS coronavirus type 2 (SARS-CoV-2) emerged in late 2019 as a zoonotic virus highly transmissible between humans that has caused the COVID-19 pandemic 1,2. This pandemic has the potential to disrupt healthcare globally and has already caused high levels of mortality, especially amongst the elderly TRANS. The overall case fatality rate for COVID-19 is estimated to be [~]2.3% overall 3 and 32.3% in hospitalized patients age TRANS 70-79 years 4. Therapeutic options for treating the underlying viremia MESHD viremia HP in COVID-19 are presently limited by a lack of effective SARS-CoV-2 antiviral drugs, although steroidal anti-inflammatory treatment can be helpful. A variety of potential antiviral targets for SARS-CoV-2 have been considered including the spike protein and replicase. Based upon previous successful antiviral drug development for HIV-1 and hepatitis C MESHD hepatitis HP, the SARS-CoV-2 main protease (Mpro) appears an attractive target for drug development. Here we show the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of [~]6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro. In our primary screen we found [~]50 compounds with activity against Mpro (overall hit rate <0.75%). Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 [≤] 50 M. Hits from our screen are enriched with hepatitis C MESHD hepatitis HP NS3/4A protease targeting drugs including Boceprevir (IC50=0.95 M), Ciluprevir (20.77M). Narlaprevir (IC50=1.10M), and Telaprevir (15.25M). These results demonstrate that some existing approved drugs can inhibit SARS-CoV-2 Mpro and that screen saturation of all approved drugs is both feasible and warranted. Taken together this work suggests previous large-scale commercial drug development initiatives targeting hepatitis C MESHD hepatitis HP NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than Boceprevir and suitable for rapid repurposing.

    Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

    Authors: Yanjin Li; Yu Zhang; Yikai Han; Tengfei Zhang; Ranran Du

    doi:10.26434/chemrxiv.12629858.v1 Date: 2020-07-09 Source: ChemRxiv

    Since its outbreak in 2019, the acute respiratory syndrome MESHD caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease MESHD. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C MESHD hepatitis HP virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome MESHD and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.

    EVALUATION OF THE ABBOTT SARS-COV-2 IG-G ASSAY.

    Authors: CS Lau; SP Hoo; YL Liang; TC Aw

    doi:10.1101/2020.06.28.20132498 Date: 2020-06-30 Source: medRxiv

    Introduction: Antibodies SERO to the novel severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) can increase as soon as 10-13 days after infection MESHD. We describe our evaluation of the Abbott SARS-CoV-2 IgG assay on the Architect immunoassay SERO analyser. Methods: We assessed the precision, sensitivity SERO, and specificity of the Abbott SARS-CoV-2 IgG assay in samples from polymerase chain reaction (PCR) positive patients and healthy healthcare workers. The manufacturer cut-off index (COI) of 1.4 was adopted to identify positive results. We examined the assay cross-reactivity with other viral antibodies SERO (influenza/ dengue MESHD/ hepatitis C MESHD hepatitis HP/ hepatitis B MESHD hepatitis HP) and rheumatoid factor (RF). The sample throughput of the Abbott assay was also assessed. Results: The Abbott assay showed excellent precision, with a CV of 3.4% for the negative control (COI = 0.06) and 1.6% for a high positive serum sample SERO (COI = 8.6). Residual serum SERO was available from 57 inpatients not initially suspected of having COVID-19, 29 of whom tested positive for SARS-CoV-2 IgG. The Abbott assay has a sensitivity SERO of 90.9-100% when tested in 54 subjects [≥]14 days post PCR positive, and a specificity of 100% (N = 358). There was no cross-reactivity with other viral antibodies SERO (influenza/ dengue MESHD/ hepatitis C MESHD hepatitis HP/ hepatitis B MESHD hepatitis HP) and RF. The Architect Abbott assay has a throughput of 100 samples in 70 minutes. Conclusion: The Abbott SARS-CoV-2 IgG assay shows excellent performance SERO that is well within FDA and CDC guidelines when testing patients [≥]14 days POS with little cross-reactivity from other viral antibodies SERO. There is some evidence that SARS-CoV-2 IgG develops early in the disease MESHD process.

    Early Hemoglobin kinetics in response to ribavirin: Safety lesson learned from Hepatitis C MESHD Hepatitis HP to CoVID-19 therapy

    Authors: Antonio Rivero-Juarez; Mario Frias; Isabel Machuca; Marina Gallo; Pedro Lopez-Lopez; Angela Camacho; Antonio Rivero

    doi:10.1101/2020.06.29.20142281 Date: 2020-06-29 Source: medRxiv

    Background: Ribavirin (RBV) is been used for SARS-CoV-2 infection MESHD. This drug is associated with a wide range of side effects, mainly anemia MESHD anemia HP, so its use in patients with potential respiratory affectation could not be appropriate. The evidences of adverse events associated with RBV-use has mainly been derived in the context of hepatitis C MESHD hepatitis HP (HCV) treatment, however the possible use of RBV in CoVID-19 patients could be limited to 14 days. Methods: Longitudinal study including HIV/HCV coinfected patients. We evaluate the hemoglobin dynamics and reductions as well as evaluate the development rate of anemia MESHD anemia HP during the first 2 weeks of therapy in HCV infected patients. Results: 189 patients were included in the study. The median hemoglobin levels were 14.6 g/dL (IQR: 13.2-15.6 g/dL) and 13.5 g/dL (IQR: 12.3-14.5 g/dL) at weeks 1 and 2 of therapy, respectively. A cumulative number of 27 (14.2%) patients developed anemia MESHD anemia HP (23 grade 1 [12.1%] and 4 grade 2 [2.1%]). We identify a baseline hemoglobin levels of 14 g/dL as the better cut-off to identify those patients with a high chance to develop anemia MESHD anemia HP. Of the 132 patients with baseline hemoglobin level >14 g/dL, 8 developed anemia MESHD anemia HP (6.1%) compared with 19 of 57 (33.3%) with hemoglobin levels lower than 14 g/dL (p < 0.001). Conclusions: Our study shows valuable information about the early hemoglobin kinetic timing in patients on RBV-therapy, that could be useful to tailor CoVID-19 treatment if RBV use is considered.

    A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19

    Authors: Fernando Santos-Beneit; Vytautas Raškevičius; Vytenis A. Skeberdis; Sergio Bordel

    doi:10.21203/rs.3.rs-36346/v1 Date: 2020-06-18 Source: ResearchSquare

    In this study we have developed a metabolic modeling approach to identify human metabolic enzymes which can be targeted for therapeutic intervention against COVID-19. A literature search was carried out in order to identify suitable inhibitors of these enzymes, which were confirmed by docking calculations. In total, 10 targets and 12 bioactive molecules have been predicted. Among the most promising molecules we identified Triacsin C, which inhibits ACSL3, and which has been shown to be very effective against different viruses, including positive-sense single-stranded RNA viruses. Similarly, we also identified the drug Celgosivir, which has been successfully tested in cells infected with different types of viruses such as Dengue MESHD, Zika, Hepatitis C MESHD Hepatitis HP and Influenza. Finally, other drugs targeting enzymes of lipid metabolism, carbohydrate metabolism or protein palmitoylation (such as propylthiouracil, 2-bromopalmitate, lipofermata, tunicamycin, benzyl isothiocyanate, tipifarnib and lonafarnib) are also proposed.

    The in vitro antiviral activity of the anti- hepatitis C MESHD hepatitis HP virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

    Authors: Carolina Q. Sacramento; Natalia Fintelman-Rodrigues; Jairo R. Temerozo; Suelen da Silva Gomes Dias; Andre C. Ferreira; Mayara Mattos; Camila R. R. Pao; Caroline S. de Freitas; Vinicius Cardoso Soares; Fernando A. Bozza; Dumith Chequer Bou-Habib; Patricia T. Bozza; Thiago Moreno L. Souza

    doi:10.1101/2020.06.15.153411 Date: 2020-06-16 Source: bioRxiv

    The infection MESHD infection by the Severe HP by the Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) causes major public health concern and economic burden. Although clinically approved drugs have been repurposed to treat individuals with 2019 Coronavirus disease MESHD (COVID-19), the lack of safety studies and limited efficiency as well jeopardize clinical benefits. Daclatasvir and sofosbuvir (SFV) are clinically approved direct-acting antivirals (DAA) against hepatitis C MESHD hepatitis HP virus (HCV), with satisfactory safety profile. In the HCV replicative cycle, daclatasvir and SFV target the viral enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV and SARS-CoV-2 motivated us to further study the activity of daclatasvir and SFV against the new coronavirus. Daclatasvir consistently inhibited the production of infectious SARS-CoV-2 virus particles in Vero cells, in the hepatoma cell line HuH-7 and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 M, respectively. Daclatasvir targeted early events during SARS-CoV-2 replication cycle and prevented the induction of IL-6 and TNF-, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection MESHD. Sofosbuvir, although inactive in Vero cells, displayed EC50 values of 6.2 and 9.5 M in HuH-7 and Calu-3 cells, respectively. Our data point to additional antiviral candidates, in especial daclatasvir, among drugs overlooked for COVID-19, that could immediately enter clinical trials.

    Predicting inhibitors for SARS-CoV-2 RNA-dependent RNA polymerase using machine learning and virtual screening

    Authors: Romeo Cozac; Nazim Medzhidov; Shinya Yuki

    id:2006.06523v1 Date: 2020-06-09 Source: arXiv

    Global coronavirus disease MESHD pandemic (COVID-19) caused by newly identified SARS- CoV-2 coronavirus continues to claim the lives of thousands of people worldwide. The unavailability of specific medications to treat COVID-19 has led to drug repositioning efforts using various approaches, including computational analyses. Such analyses mostly rely on molecular docking and require the 3D structure of the target protein to be available. In this study, we utilized a set of machine learning algorithms and trained them on a dataset of RNA-dependent RNA polymerase (RdRp) inhibitors to run inference analyses on antiviral and anti-inflammatory drugs solely based on the ligand information. We also performed virtual screening analysis of the drug candidates predicted by machine learning models and docked them against the active site of SARS- CoV-2 RdRp, a key component of the virus replication machinery. Based on the ligand information of RdRp inhibitors, the machine learning models were able to identify candidates such as remdesivir and baloxavir marboxil, molecules with documented activity against RdRp of the novel coronavirus. Among the other identified drug candidates were beclabuvir, a non-nucleoside inhibitor of the hepatitis C MESHD hepatitis HP virus (HCV) RdRp enzyme, and HCV protease inhibitors paritaprevir and faldaprevir. Further analysis of these candidates using molecular docking against the SARS-CoV-2 RdRp revealed low binding energies against the enzyme active site. Our approach also identified anti-inflammatory drugs lupeol, lifitegrast, antrafenine, betulinic acid, and ursolic acid to have potential activity against SARS-CoV-2 RdRp. We propose that the results of this study are considered for further validation as potential therapeutic options against COVID-19.

    Combined Use of Amentoflavone and Ledipasvir Could Interfere with Binding of Spike Glycoprotein of SARS-CoV-2 to ACE2: The Results of Molecular Docking Study

    Authors: Kateryna Miroshnychenko; Anna V. Shestopalova

    doi:10.26434/chemrxiv.12377870.v1 Date: 2020-05-29 Source: ChemRxiv

    In this study we used molecular docking method to test 248 drugs related to the virus research against spike glycoprotein of SARS-CoV-2. For ten top-ranked drugs the binding sites and interactions with spike glycoprotein were analyzed in detail. The best-scored ligand is the natural biflavonoid amentoflavone. Nine of twelve top-ranked ligands are drugs used for hepatitis C MESHD hepatitis HP treatment. Among them are ledipasvir, paritaprevir, elbasvir, simeprevir, velpatasvir, glecaprevir and pibrentasvir. The two first-ranked ligands (amentoflavone and ledipasvir) have different binding sites, so their combined use may be effective, but the careful testing is required. We encourage other researchers to explore the combination of amentoflavone and ledipasvir against SARS-CoV-2 in vitro and in vivo.

    Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir

    Authors: Ho Sing Lo; Kenrie P. Y. Hui; Hei-Ming Lai; Khadija Shahed Khan; Simranjeet Kaur; Zhongqi Li; Anthony K. N. Chan; Hayley Hei-Yin Cheung; Ka Chun Ng; John Chi Wang Ho; Yu Wai Che; Bowen Ma; Peter Man-Hin Cheung; Donghyuk Shin; Kaidao Wang; Kuen-Phon Wu; Ivan Dikic; Po-Huang Liang; Zhong Zuo; Francis K. L. Chan; David S. C. Hui; Vincent C. T. Mok; Kam-Bo Wong; Ho Ko; Wei Shen Aik; Michael C. W. Chan; Wai-Lung Ng

    doi:10.1101/2020.05.26.116020 Date: 2020-05-26 Source: bioRxiv

    The recent outbreak of coronavirus disease MESHD 2019 (COVID-19), caused by the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) virus, is a global threat to human health. By in vitro screening and biochemical characterization, we identified the hepatitis C MESHD hepatitis HP virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. We also revealed that simeprevir synergizes with the RNA-dependent RNA polymerase (RdRP) inhibitor remdesivir to suppress the replication of SARS-CoV-2 in vitro. Our results provide preclinical rationale for the combination treatment of simeprevir and remdesivir for the pharmacological management of COVID-19 patients. One Sentence SummaryDiscovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes remdesivir.

    Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

    Authors: Vaishali Chandel; Prem Prakash Sharma; Sibin Raj; Brijesh Rathi; Dhruv Kumar

    doi:10.26434/chemrxiv.12292514.v1 Date: 2020-05-14 Source: ChemRxiv

    Due to unavailability of therapeutic approach for the novel coronavirus disease MESHD (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease MESHD. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti- tuberculosis MESHD and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C MESHD hepatitis HP virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection MESHD and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, in vitro and in vivo validation of these findings will be helpful in bringing these molecules at the clinical settings.

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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