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    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.

    Different selection dynamics of S and RdRp PROTEIN between SARS-CoV-2 genomes with and without the dominant mutations

    Authors: Necla Koçhan; Doğa Eskier; Asli Suner; Gökhan Karakülah; Yavuz Oktay

    doi:10.1101/2021.01.03.20237602 Date: 2021-01-05 Source: medRxiv

    SARS-CoV-2 is a betacoronavirus responsible for the COVID-19 pandemic MESHD that has affected millions of people worldwide, with no dedicated treatment or vaccine currently available. As pharmaceutical research against and the most frequently used tests for SARS-CoV-2 infection MESHD both depend on the genomic and peptide sequences of the virus for their efficacy, understanding the mutation rates and content of the virus is critical. Two key proteins for SARS-CoV-2 infection MESHD and replication are the S protein PROTEIN, responsible for viral entry into the cells, and RdRp PROTEIN, the RNA polymerase responsible for replicating the viral genome. Due to their roles in the viral cycle, these proteins are crucial for the fitness MESHD and infectiousness of the virus. Our previous findings had shown that the two most frequently observed mutations in the SARS-CoV-2 genome, 14408C>T in the RdRp PROTEIN coding region, and 23403A>G in the S gene, are correlated with higher mutation density over time. In this study, we further detail the selection dynamics and the mutation rates of SARS-CoV-2 genes, comparing them between isolates carrying both mutations, and isolates carrying neither. We find that the S gene and the RdRp PROTEIN coding region show the highest variance between the genotypes, and their selection dynamics contrast each other over time. The S gene displays higher positive selection in mutant isolates early on, and undergoes increasing negative selection over time, whereas the RdRp PROTEIN region in the mutant isolates shows strong negative selection throughout the pandemic.

    Global surveillance of potential antiviral drug resistance in SARS-CoV-2: proof of concept focussing on the RNA-dependent RNA polymerase PROTEIN

    Authors: Alfredo Mari; Tim-Christoph Roloff; Madlen Stange; Kirstine Kobberoee Soegaard; Erblin Asllanaj; Gerardo Tauriello; Leila Tamara Alexander; Michael Schweitzer; Karoline Leuzinger; Alexander Gensch; Aurelien Martinez; Julia Bielicki; Hans Pargger; Martin Siegemund; Christian Nickel; Roland Bingisser; Michael Osthoff; Stefano Bassetti; Parham Sendi; Manuel Battegay; Catia Marzolini; Helena Seth-Smith; Torsten Schwede; Hans H. Hirsch; Adrian Egli

    doi:10.1101/2020.12.28.20248663 Date: 2021-01-04 Source: medRxiv

    Antiviral treatments for COVID-19 MESHD have involved many repurposed drugs. Currently, SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors with debated clinical impact. Among these, remdesivir has been conditionally approved for the treatment of COVID-19 MESHD patients. Although the emergence of antiviral resistance, an indirect proxy for antiviral efficacy, poses a considerable healthcare threat, an evolutionary perspective on emerging resistant mutants is still lacking. Here we show that SARS-CoV-2 RdRp PROTEIN is under purifying selection, that potential escape mutations are rare, and unlikely to lead to viral fitness loss MESHD. In more than 56,000 viral genomes from 105 countries dating from December 2019 to July 2020 we found negative selective pressure affecting nsp12 (Tajimas D = -2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Those affected known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations found globally, in silico structural models show that this rarely implies loss of stability in RdRp PROTEIN. No potential escape mutation were found in our local cohort of remdesivir treated patients from the first wave (n=8). Our results indicate that RdRp PROTEIN is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. Our study could be the starting point of a larger monitoring effort of drug resistance throughout the COVID-19 pandemic MESHD. We recommend the application of repetitive genome sequencing of SARS-CoV-2 from patients treated with antivirals to provide early insights into the evolution or antiviral resistance.

    Comparative analysis of loop-mediated isothermal amplification (LAMP)-based assays for rapid detection of SARS-CoV-2 genes

    Authors: Daniel Urrutia-Cabrera; Roxanne Hsiang-Chi Liou; Jianxiong Chan; Sandy Shen-Chi Hung; Alex W Hewitt; Keith Martin; Patrick Kwan; Raymond Ching-Bong Wong

    doi:10.1101/2020.12.21.20248288 Date: 2020-12-22 Source: medRxiv

    The COVID-19 pandemic MESHD caused by SARS-CoV-2 has infected millions worldwide and there is an urgent need to increase our diagnostic capacity to identify infected cases. Although RT-qPCR remains the gold standard for SARS-CoV-2 detection, this method requires specialised equipment in a diagnostic laboratory and has a long turn-around time to process the samples. To address this, several groups have recently reported development of loop-mediated isothermal amplification (LAMP) as a simple, low cost and rapid method for SARS-CoV-2 detection. Herein we present a comparative analysis of three LAMP-based assays that target different regions of the SARS-CoV-2: ORF1ab PROTEIN RdRP PROTEIN, ORF1ab PROTEIN nsp3 HGNC and Gene N PROTEIN. We perform a detailed assessment of their sensitivity, kinetics and false positive rates for SARS-CoV-2 diagnostics in LAMP or RT-LAMP reactions, using colorimetric or fluorescent detection. Our results independently validate that all three assays can detect SARS-CoV-2 in 30 minutes, with robust accuracy at detecting as little as 1000 RNA copies and the results can be visualised simply by color changes. We also note the shortcomings of these LAMP-based assays, including variable results with shorter reaction time or lower load of SARS-CoV-2, and false positive results in some experimental conditions. Overall for RT-LAMP detection, the ORF1ab PROTEIN RdRP PROTEIN and ORF1ab PROTEIN nsp3 HGNC assays have higher sensitivity and faster kinetics for detection, whereas the Gene N PROTEIN assay exhibits no false positives in 30 minutes reaction time. This study provides validation of the performance of LAMP-based assays for SARS-CoV-2 detection, which have important implications in development of point-of-care diagnostic for SARS-CoV-2.

    Routine SARS-CoV-2 wastewater surveillance results in Turkey to follow Covid-19 MESHD outbreak

    Authors: Bilge Alpaslan Kocamemi; Halil Kurt; Ahmet Sait; Hamza Kadi; Fahriye Sarac; Ismail Aydin; Ahmet Mete Saatci; Bekir Pakdemirli

    doi:10.1101/2020.12.21.20248586 Date: 2020-12-22 Source: medRxiv

    A global pandemic of Coronavirus Disease 2019 MESHD ( Covid-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SAR-CoV-2) declared by WHO in March 2019 is still ongoing. As of 13th of December 2020, 70 million people were infected by SARS-CoV-2 and 1.5 million people lost their lives globally (WHO, 2020). Since March 2019, diagnosis of Covid-19 MESHD cases has been done through PCR test of samples from nasopharyngeal and throat swabs. However, in March 2019, it was reported that the faeces [1] and urine [2] of all infected people contain SARS-CoV-2 MESHD. Later, numerous researchers [3-7] detected SARS-CoV-2 in faeces of both symptomatic and asymptomatic patients. Moreover, some studies [1,4,8-12] suggested the possibility of extended duration of viral shedding in faeces after the patients respiratory samples tested negative. In this respect, SARS-CoV-2 wastewater-based epidemiology (WBE), i.e., wastewater surveillance, aiming to estimate the distribution of asymptomatic and symptomatic individuals in a specific region has received worldwide attention. Various research groups worldwide [1, 13-54] have started SARS-CoV-2 detection in wastewater since WBE provides tracking whole population by testing a small number of wastewater samples in a specific region and can predict SARS-CoV-2 RNA in human faeces a few days to a week before onset of symptoms. This makes WBE quite economic tool for continual tracking of decreasing or increasing trend of the Covid-19 MESHD in a particular region. However, up to date, almost all of the WBE studies have been performed with samples from a few treatment plants. There was no reported nationwide wastewater surveillance study that has been integrated into a national Covid-19 MESHD management strategy by decision makers. Nationwide, SARS-CoV-2 surveillance studies have great potential to reflect the actual distribution of Covid-19 MESHD cases in a community by accounting not only symptomatic patients tested but also asymptomatic patients having no or mild symptoms and not been tested. As opposed to clinical surveillance studies, wastewater-based surveillance studies will reflect the number of cases in a community by testing one sample from a treatment plant serving this community instead of performing individual swab tests. Turkey, which is among the few countries that started wastewater based surveillance studies at the early stages of pandemic is a leading country, performing a nationwide surveillance study. The distribution of Covid-19 MESHD cases throughout the country via SARS-CoV-2 measurements in influent, effluent and sludge samples of wastewater treatment plants (WWTPs) located in 81 cities through May 2020- June 2020 was conducted [36, 51, 52]. In June 2020, nationwide routine sampling through 22 regional identified cities has been started. However, from June to September 2020 all samples were detected negative due to problems with RT-pCR primer targeting RdRp PROTEIN gene of SARS-CoV-2 genome. Since September 2020, routine sampling from 22 cities of Turkey with 2 weeks sampling period (weekly for mega city Istanbul) has been continued and regional Covid-19 MESHD distributions have been reported as viral loads on color-scale maps. To the best our knowledge, this is the first routine nationwide surveillance study indicating Covid-19 MESHD distribution regularly using color-scale presentation on a map.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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