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    In vitro evolution of Remdesivir resistance reveals genome plasticity of SARS-CoV-2

    Authors: Agnieszka M Szemiel; Andres Merits; Richard J Orton; Oscar MacLean; Arthur Wickenhagen; Gauthier Lieber; Rute Maria Pinto; Matthew L Turnbull; Sainan Wang; Daniel Mair; Ana da Silva Filipe; Brian J Willett; Sam J Wilson; Arvind H Patel; Emma C Thomson; Massimo Palmarini; Alain Kohl; Meredith E Stewart

    doi:10.1101/2021.02.01.429199 Date: 2021-02-10 Source: bioRxiv

    Remdesivir (RDV) is used widely for COVID-19 MESHD patients despite varying results in recent clinical trials. Here, we show how serially passaging SARS-CoV-2 in vitro in the presence of RDV selected for drug-resistant viral populations. We determined that the E802D mutation in the RNA-dependent RNA polymerase PROTEIN was sufficient to confer decreased RDV sensitivity without affecting viral fitness MESHD. Analysis of more than 200,000 sequences of globally circulating SARS-CoV-2 variants show no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we also observed changes in the Spike (i.e., H69 E484, N501, H655) corresponding to mutations identified in emerging SARS-CoV-2 variants indicating that they can arise in vitro in the absence of immune selection. This study illustrates SARS-CoV-2 genome plasticity and offers new perspectives on surveillance of viral variants.

    In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp MESHD RdRp PROTEIN

    Authors: Khushboo Pandey; Kiran Bharat Lokhande; K. venkateswara Swamy; Shuchi Nagar; Manjusha Dake

    doi:10.21203/rs.3.rs-225174/v1 Date: 2021-02-09 Source: ResearchSquare

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp PROTEIN of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp MESHD RdRp PROTEIN, they were subjected to molecular docking, 100ns molecular dynamics ( MD MESHD) simulation followed by post-simulation analysis. Further, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp PROTEIN revealed that, EBDGp possess stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity towards SARS-CoV-2 RdRp MESHD RdRp PROTEIN. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp MESHD RdRp PROTEIN. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp PROTEIN-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

    Increased SAR-CoV-2 shedding associated with reduced disease severity despite continually emerging genetic variants

    Authors: Cynthia Y Tang; Yang Wang; Cheng Gao; David R Smith; Jane A McElroy; Tao Li; Karen Segovia; Tricia Haynes; Richard Hammer; Christopher Sampson; Detlef Ritter; Christopher Schulze; Robin Trotman; Grace M Lidl; Richard Webby; Jun Hang; Xiu-Feng Wan

    doi:10.1101/2021.02.03.21250928 Date: 2021-02-05 Source: medRxiv

    Since the first report of SARS-CoV-2 in December 2019, genetic variants have continued to emerge, complicating strategies for mitigating the disease burden of COVID-19 MESHD. In this study, we investigated the emergence and spread of SARS-CoV-2 genetic variants in Missouri, examined viral shedding over time, and analyzed the associations among emerging genetic variants, viral shedding, and disease severity. The study population included COVID-19 MESHD positive patients from CoxHealth (Springfield, Missouri) and University of Missouri Health Care (UMHC; Columbia, Missouri) between March and October 2020. All positive SARS-CoV-2 nasopharyngeal swabs (n=8,735) from March-October 2020 were collected. Available viral genomes (n=184) from March to July were sequenced. Hospitalization status and length of stay were extracted from medical charts of 1,335 patients (UMHC and sequenced patients). The primary outcome was hospitalization status (yes or no) and length of hospital stay (days). For the 1,335 individuals, 44 were hospitalized and four died due to COVID-19 MESHD. The average age was 34.35 (SD=16.82), with 55.1% females (n=735) and 44.7% males (n=596). Multiple introductions of SARS-CoV-2 into Missouri, primarily from Australia, Europe, and domestic states, were observed. Four local lineages rapidly emerged and spread across urban and rural regions in Missouri. While most Missouri viruses harbored Spike-D614G mutations, many unreported mutations were identified among Missouri viruses, including seven in the RNA-dependent RNA polymerase PROTEIN complex and Spike protein PROTEIN that were positively selected. A 15.6-fold increase in viral RNA levels in swab samples occurred from March to May and remained elevated through October. Accounting for comorbidities, individuals test-positive for COVID-19 MESHD with high viral loads were less likely to be hospitalized (odds ratio=0.39, 95% confidence interval=0.20, 0.77) and more likely to be discharged from the hospital sooner (hazard ratio=2.9, p=0.03) than those with low viral loads. Overall, the first eight months of the pandemic in Missouri saw multiple locally acquired mutants emerge and dominate in urban and rural locations. Although we were unable to find associations between specific variants and greater disease severity, Missouri COVID-positive individuals that presented with increased viral shedding had less severe disease by several measures.

    Characterization of the NiRAN domain from RNA-dependent RNA polymerase PROTEIN provides insights into a potential therapeutic target against SARS-CoV-2

    Authors: Abhisek Dwivedy; Richard Mariadasse; Mohammed Ahmad; Sayan Chakraborty; Deepsikha Kar; Satish Tiwari; Tanmay Majumdar; Jeyaraman Jeyakanthan; Bichitra Biswal

    doi:10.1101/2021.02.03.429510 Date: 2021-02-03 Source: bioRxiv

    Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases PROTEIN ( RdRp PROTEIN) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp PROTEIN associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp PROTEIN from the severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness as well as DFT properties. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp PROTEIN. Interestingly, the proposed kinase inhibitors and a few of the predicted nucleotidyl transferase inhibitors significantly inhibited the aforementioned enzymatic activity. In line with the current global COVID-19 pandemic MESHD urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

    Lost in translation: codon optimization inactivates SARS-CoV-2 RdRp PROTEIN

    Authors: Bing Wang; Vladimir Svetlov; Evgeny Nudler; Irina Artsimovitch

    doi:10.1101/2021.01.24.428004 Date: 2021-01-25 Source: bioRxiv

    RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) is a primary target for antivirals. We report that Nsp12, a catalytic subunit of SARS-CoV-2 RdRp MESHD RdRp PROTEIN, produces an inactive enzyme when codon-optimized for bacterial expression. We also show that accessory subunits, NTPs, and translation by slow ribosomes partially rescue Nsp12. Our findings have implications for functional studies and identification of novel inhibitors of RdRp PROTEIN and for rational design of other biotechnologically and medically important expression systems.

    Existence of SARS-CoV-2 RNA on ambient particulate matter samples: A nationwide study in Turkey

    Authors: Ozgecan Kayalar; Akif Ari; Gizem Babuccu; Nur Konyalilar; Ozlem Dogan; Fusun Can; Ulku Alver Sahin; Eftade Gaga; Levent Kuzu; Pelin Ari; Mustafa Odabasi; Yucel Tasdemir; Siddik Cindoruk; Fatma Esen; Egemen Sakin; Burak Caliskan; Lokman Tecer; Merve Ficici; Ahmet Altin; Burcu Onat; Coskun Ayvaz; Burcu Uzun; Arslan Saral; Tuncay Dogeroglu; Semra Malkoc; Ozlem Uzmez; Fatma Kunt; Senar Aydin; Melik Kara; Baris Yaman; Guray Dogan; Bihter Olgun; Ebru Dokumaci; Gulen Gullu; Elif Uzunpinar; Hasan Bayram

    doi:10.1101/2021.01.24.21250391 Date: 2021-01-25 Source: medRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by the SARS-CoV-2 virus MESHD and has been affecting the world since the end of 2019. Turkey is severely affected with the first case being reported on March 11th 2020. Ambient particulate matter (PM) samples in various size ranges were collected from 13 sites including urban and urban background locations and hospital gardens in 10 cities across Turkey between the 13th of May and the 14th of June, 2020 to investigate a possible presence of SARS-CoV-2 RNA on ambient PM. A total of 155 daily samples (TSP, n=80; PM2.5, n=33; PM2.5-10, n=23; PM10, n=19; and 6 size segregated, n=48) were collected using various samplers in each city. The N1 gene and RdRP PROTEIN gene expressions were analyzed for the presence of SARS-CoV-2 as suggested by the Centers for Disease Control and Prevention (CDC). According to RT-PCR and 3D-RT-PCR analysis, dual RdRP PROTEIN and N1 gene positivity were detected in 20 (9.8 %) of the samples. The highest percentage of virus detection on PM samples was from hospital gardens in Tekirda[g], Zonguldak, and [I]stanbul--especially in PM2.5 mode. Samples collected from two urban sites were also positive. Findings of this study have suggested that SARS-CoV-2 may be transported by ambient particles especially at sites close to the infection hot-spots. However, whether this has an impact on the spread of the virus infection MESHD remains to be determined. Significance StatementAlthough there are several studies reporting the existence of SARS-CoV-2 in indoor aerosols is established, it remains unclear whether the virus is transported by ambient atmospheric particles. The presence of the SARS-CoV-2 RNA in ambient particles collected from characteristic sites within various size ranges was investigated, and positive results were found in urban sites especially around Turkish hospitals. In this context, this study offers a new discussion on the transmission of the virus via ambient particles.

    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.

    In vitro screening of anti-viral and virucidal effects against SARS-CoV-2 by Hypericum perforatum and Echinacea.

    Authors: Leena Hussein Bajrai; Sherif Ali El-kafrawy; Rabie Saleh Alnahas; Esam Ibraheem Azhar; Ayush Jain; Roman Sarkar; Abhishek Dubey; Syed Azeez Tehseen; Sharvan Sehrawat; Florian Douam; Nicholas Crossland; Madison M Hebert; Scott W Benzinger; Koushik T Sinha; Keith T Gagnon; Rafael Rezende; Eduardo Cilli; Guilherme Malafaia; Nicholas Thomson; Caroline Buckee; Firdausi Qadri; Tahmina Shirin

    doi:10.1101/2021.01.11.426295 Date: 2021-01-13 Source: bioRxiv

    Special Infectious Agent Unit in King Fahd Medical Research Center at King Abdulaziz University, Jeddah, Saudi Arabia, has pursed the anti-viral project field to optimize the group of medicinal plants for human-infectious diseases. We have begun virtually in this field since COVID-19 pandemic MESHD, besides our divergence in the infectious agents. In this study and based on the previous review, Hypericum perforatum (St. Johns Wort) and Echinacea (gaia HERBS(R)) were tested in vitro using Vero E6 cells for their anti-viral effects against the newly identified Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2) through its infectious cycle from 0 to 48 hours post infection. The hypericin (0.9 mg) of H. perforatum and the different parts (roots, seeds, aerial) of two types of Echinacea species (Echinacea purpurea and Echinacea angustifolia) were examined their efficacy in certain concentration and under light-dependent anti-viral activities to measure the inhibition of the SARS-CoV-2 mRNA expression of RNA-dependent RNA polymerase PROTEIN ( RdRP PROTEIN) gene and the viral load with quantitative real-time polymerase chain reaction (qRT-PCR), and to assess the neutralization of the SARS-CoV-2 spike PROTEIN receptor binding on cell culture assay. Interestingly, the mixture (H.E.) of 100 mg/mL of H. perforatum and Echinacea was tested too on SARS-CoV-2 and showed crucial anti-viral activity competing H. perforatum then Echinacea effects as anti-viral treatment. Therefore, the results of gaia HERBS(R) products, H. perforatum and Echinacea species, applied in this study showed significant anti-viral and virucidal effects in the following order of potency: H. perforatum, H.E., and Echinacea on SARS-CoV-2 infectious cycle; and will definitely required a set up of clinical trial with specific therapeutic protocol based on the outcome of this study. Author SummaryAfter an outbreak of Rift Valley Fever MESHD in the Southern region of Saudi Arabia, particularly in May 2003, Special Infectious Agents Unit (SIAU) was established and founded by Prof. Esam Ibraheem Azhar. This unit contains a full range of facilities including Biosafety Level 3, allows him and his research groups to ambulate and culture risk group 3 viruses in Saudi Arabia & Gulf States for the first time. Since that time, SIAU MESHD and our international collaboration have been extended to implement a standard protocols in the infectious agents diagnostics procedure through different mode of collaboration including exchange of expertise, joint research program and more recently a technology transfer agreements with number of international institute sharing same interests. Furthermore, we have been engaged in number of researches related to Hajj & Umrah plus number of national services with the Ministry of Health (MOH) through which, we utilize our Mobile biosafety level 3 Lab to enhance the diagnostics of MERS CoV in the Holly sites during Hajj since 2014. In our SIAU and with a powerful team, we have excellent researches made valuable contributions through in vivo and in vitro animal and human studies, and several human viral pathogens which are a threat to global health security due to millions of pilgrims visiting Saudi Arabia every year from 182 countries: with particular areas of interests in: Alkhurma Viral Hemorrhagic Fever MESHD, Dengue Hemorrhagic Fever Viruses, Rift Valley Fever Virus, MERS-CoV MESHD and more recently the new global infectious diseases threat, Sever Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2).

    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.

    Early Onset Favipiravir Saves Lives

    Authors: Ercan KARATAS; Lacin Aksoy; Pinar Elbir Kilic; Arzu Dogru; Ersin Ozaslan

    doi:10.21203/rs.3.rs-142868/v1 Date: 2021-01-07 Source: ResearchSquare

    Background Favipiravir, an antiviral recommended for use in patients with tachypnea MESHD (respiratory rate 30 / min) in COVID-19 MESHD pneumonia MESHD, with SpO2 level below 90% in room air and with bilateral diffuse pneumonia MESHD on chest X-ray or tomography, or patients with treatment-resistant fever MESHD, is a new type of RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) inhibitor. After the administration of Favipiravir, it contributed significantly to reducing mortality in patients with severe COVID-19 MESHD positive disease. We performed this study to determine the start time in Favipiravir's covid pneumonia.Material MESHD and Method: We evaluated the effect of a total of 5 days of oral treatment as a 2 × 1600 mg loading dose and a 2 × 600 mg maintenance dose of Favipiravir added to the standard COVID-19 MESHD treatment received by patients with laboratory-radiology-clinical findings who have advanced or severe COVID 19 pneumonia MESHD.Results 180 patients hospitalized at Tuzla State Hospital and given Favipiravir treatment between 20/3/2020 and 30/5/2020 were examined. As of hospitalization, 17 of 101 patients (17%) who were given Favipiravir treatment in ≤ 3 days died, 30 of 79 patients (38%) who were given Favipiravir treatment for in > 3 days died (p:0.002). 33 of 47 patients (70%) who died were > 65 years old. Only 5 of the 47 (11%) patients who died had no comorbid disease. 35 had two or more comorbid diseases.Conclusion Patients with radiological findings indicating that COVID-19 MESHD will be severe and laboratory findings at the time of the first 3 days should be initiated with an effective dose of Favipiravir treatment without waiting for the clinical worsening.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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