Corpus overview


MeSH Disease

Human Phenotype


    displaying 1 - 9 records in total 9
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    Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells

    Authors: Xammy Nguyenla; Eddie Wehri; Erik Van Dis; Scott Biering; Livia H Yamashiro; Julien Stroumza; Claire Dugast-Darzacq; Thomas Graham; Sarah Stanley; Julia Schaletzky; Jingya Wang; Joht Singh Chandan; Christopher Sainsbury; Dawit Tefra Zemedikun; G Neil Thomas; Dhruv Parekh; Tom Marshall; Elizabeth Sapey; Nicola J Adderley; Krishnarajah Nirantharakumar; Ricardo Soto-Rifo; Fernando Valiente-Echeverría; Christian Caglevic; Mauricio Mahave; Carolina Selman; Raimundo Gazitúa; José Luis Briones; Franz Villarroel-Espindola; Carlos Balmaceda; Manuel A. Espinoza; Jaime Pereira; Bruno Nervi

    doi:10.1101/2020.09.18.302398 Date: 2020-09-18 Source: bioRxiv

    The SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with currently 29 million confirmed cases TRANS and close to a million deaths. At this time, there are no FDA-approved vaccines or therapeutics for COVID-19, but Emergency Use Authorization has been granted for remdesivir, a broad-spectrum antiviral nucleoside analog. However, remdesivir is only moderately efficacious against SARS-CoV-2 in the clinic, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. We identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis HP Hepatitis MESHD C virus nonstructural protein 5 A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency 25-fold. We therefore suggest that the FDA-approved Hepatitis HP Hepatitis MESHD C therapeutics Epclusa (velpatasvir/sofosbuvir) and Zepatier (elbasvir/grazoprevir) should be fast-tracked for clinical evaluation in combination with remdesivir to improve treatment of acute SARS-CoV-2 infections MESHD.

    Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases MESHD

    Authors: Michael Westberg; Yichi Su; Xinzhi Zou; Brett Hurst; Bart Tarbet; Michael Lin; Christophe Parizot; Delphine Sauce; Julien Mayaux; Charles-Edouard Luyt; Alexandre Boissonnas; Zahir Amoura; Valerie Pourcher; Makoto Miyara; Guy Gorochov; Amelie Guihot; Christophe Combadiere; Duraipandian Thavaselvam; Devendra Kumar Dubey; Paul Lin; Hila Shaim; Sean G Yates; David Marin; Indreshpal Kaur; Sheetal Rao; Duncan Mak; Angelique Lin; Qi Miao; Jinzhuang Dou; Ken Chen; Richard Champlin; Elizabeth J Shpall; Katayoun Rezvani

    doi:10.1101/2020.09.15.275891 Date: 2020-09-15 Source: bioRxiv

    The main protease, Mpro, of SARSCoV2 is a key protein in the coronavirus life cycle and a major drug target. Based on crystal structures of SARSCoV2 Mpro complexed with peptidomimetic inhibitors, we recognized a structural motif shared with approved inhibitors of hepatitis HP hepatitis MESHD C virus protease. Initial tests showed that several HCV protease inhibitors could indeed also inhibit Mpro. Based on the identified molecular scaffolds we designed a new generation of ketoamide-based Mpro inhibitors with a preorganized backbone conformation. One of the designed inhibitors, ML1000, shows particularly high affinity towards Mpro and inhibits SARSCoV2 viral replication in human cells at sub-micromolar concentrations. Our findings identify ML1000 as a promising new scaffold for the development of anti-coronavirus drugs.


    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 coronavirus 2 MESHD (SARS-CoV-2) can increase as soon as 10-13 days after infection MESHD. We describe our evaluation of the Abbott SARS-CoV-2 MESHD IgG assay on the Architect immunoassay SERO analyser. Methods: We assessed the precision, sensitivity SERO, and specificity of the Abbott SARS-CoV-2 MESHD 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/ hepatitis HP hepatitis MESHD C/ hepatitis HP B) and rheumatoid MESHD 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/ hepatitis HP hepatitis MESHD C/ hepatitis HP B) and RF. The Architect Abbott assay has a throughput of 100 samples in 70 minutes. Conclusion: The Abbott SARS-CoV-2 MESHD 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 process.

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

    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 by the Severe HP acute respiratory syndrome coronavirus 2 MESHD (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 HP hepatitis MESHD C virus ( HCV MESHD), with satisfactory safety profile. In the HCV MESHD 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 MESHD NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV MESHD 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 MESHD virus particles in Vero cells, in the hepatoma MESHD 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 MESHD 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 HP hepatitis MESHD C virus ( HCV MESHD) RdRp enzyme, and HCV MESHD 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 MESHD. We propose that the results of this study are considered for further validation as potential therapeutic options against COVID-19.

    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 coronavirus 2 MESHD (SARS-CoV-2) virus, is a global threat to human health. By in vitro screening and biochemical characterization, we identified the hepatitis HP hepatitis MESHD C virus ( HCV MESHD) 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.

    First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients

    Authors: Hongyi Chen; Zhicheng Zhang; Li Wang; Zhihua Huang; Fanghua Gong; Xiaodong Li; Yahong Chen; Jinzi J. WU

    doi:10.1101/2020.03.22.20034041 Date: 2020-03-24 Source: medRxiv

    As coronavirus disease MESHD 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), started in China in January, 2020, repurposing approved drugs is emerging as important therapeutic options. We reported here the first clinical study using hepatitis HP hepatitis MESHD C virus (HCV) protease inhibitor, danoprevir, to treat COVID-19 patients. Danoprevir (Ganovo) is a potent HCV protease (NS3/4A) inhibitor (IC50 = 0.29 nM), which was approved and marketed in China since 2018 to treat chronic hepatitis HP hepatitis C MESHD patients. Ritonavir is a CYP3A4 inhibitor to enhance plasma SERO concentration of danoprevir while it also acts as a human immunodeficiency HP immunodeficiency MESHD virus ( HIV MESHD) protease inhibitor at high doses. The chymotrypsin-like protease of SARS-CoV-2 shares structure similarity with HCV MESHD and HIV MESHD proteases. In the current clinical study (NCT04291729) conducted at the Nineth Hospital of Nanchang, we evaluated therapeutic effects of danoprevir, boosted by ritonavir, on treatment naive and experienced COVID-19 patients. The data from this small-sample clinical study showed that danoprevir boosted by ritonavir is safe and well tolerated in all patients. After 4 to 12-day treatment of danoprevir boosted by ritonavir, all eleven patients enrolled, two naive and nine experienced, were discharged from the hospital as they met all four conditions as follows: (1) normal body temperature for at least 3 days; (2) significantly improved respiratory symptoms; (3) lung imaging shows obvious absorption and recovery of acute exudative lesion; and (4) two consecutive RT-PCR negative tests of SARS-CoV-2 nucleotide acid (respiratory track sampling with interval at least one day). Our findings suggest that repurposing danoprevir for COVID-19 is a promising therapeutic option.

    Simeprevir, Potential Candidate to Repurpose for Coronavirus Infection: Virtual Screening and Molecular Docking Study

    Authors: Faezeh Sadat Hosseini; Massoud Amanlou

    id:10.20944/preprints202002.0438.v1 Date: 2020-02-28 Source:

    Coronavirus disease MESHD 2019 (COVID-19) has been first appeared in Wuhan, China but its fast transmission TRANS, led to its widespread prevalence SERO in various countries and make it a global concern. In addition, lack of a definitive treatment is another concern that needs to be attention. Researchers have come up with several options, which are not certain, but protease inhibitor and some antiviral agent are in the forefront. In this study a virtual screening procedure employing docking of different databases including 1615 FDA approved drugs was used to identify new potential small molecule inhibitors for protease protein of COVID-19. The docking result indicates that among all, simeprevir ( Hepatitis HP Hepatitis MESHD C virus ( HCV MESHD) NS3/4A protease inhibitor) could fit well to the binding pocket of protease and because of some other positive features including ADME profile, might be a helpful treatment option for COVID-19.

    Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)

    Authors: Abdo Elfiky; Noha S Ibrahim

    doi:10.21203/rs.2.23280/v1 Date: 2020-02-10 Source: ResearchSquare

    A new mysterious coronavirus outbreak started last month in China. The World Health Organization (WHO) termed the new virus strain 2019-nCoV to be the seventh reported human coronaviruses (HCoV). A seafood market in Wuhan city, central China was the starting point of the emergence with unknown animal causes the first animal to human infection MESHD. Until today 904 confirmed deaths MESHD and more than 40000 cases confirmed TRANS in China and 28 countries. There is a massive fear of the human to human transmission TRANS of 2019-nCoV that reported last week by the Chinese government. The most famous two strains of HCoV are the Severe Acute Respiratory Syndrome coronavirus (SARS CoV) and the Middle East Respiratory Syndrome coronavirus (MERS CoV) MESHD. The former had emerged in China in 2002 while the latter emerged in the Middle East region in 2012 and south Korea in 2015. In this study, the newly emerged 2019-nCoV papain-like protease (PLpro) is targeted by anti-SARS PLpro drugs and the anti- Hepatitis HP Hepatitis MESHD C Virus (HCV) Non-structural protein 3 (NS3) serine protease drugs. Sequence analysis, modeling, and docking are used to get a valid model for 2019-nCoV PLpro. The results suggest the effectiveness of the anti-SARS drugs (GRL-0667, GRL-0617, and Mycophenolic acid) and the anti-HCV drugs (Grazoprevir, Telaprevir, and Boceprevir) as potent inhibitors against the newly emerged coronavirus.  

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MeSH Disease
Human Phenotype

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