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    In silico Screening of Food Bioactive Compounds to Predict Potential Inhibitors of COVID-19 MESHD Main protease PROTEIN ( Mpro PROTEIN) and RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN)

    Authors: Brahmaiah Pendyala; Ankit Patras

    doi:10.26434/chemrxiv.12051927.v2 Date: 2020-04-03 Source: ChemRxiv

    As novel corona virus ( COVID-19 MESHD) infections has spread throughout the world, world health organization (WHO) has announced COVID-19 MESHD as a pandemic infection. Henceforth investigators are conducting extensive research to find possible therapeutic agents against COVID-19 MESHD. Main protease PROTEIN ( Mpro PROTEIN) that plays an essential role in processing the polyproteins that are translated from the 2019-nCOV RNA and RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) that catalyzes the replication of RNA from RNA template becomes as a potential targets for in silico screening of effective therapeutic compounds to COVID-19 MESHD. In this study we used COVID-19 MESHD Docking Server to predict potential food bioactive compounds to inhibit Mpro PROTEIN and RdRp PROTEIN. The results showed that Phycocyanobilin, Riboflavin, Cyanidin, Daidzein, Genistein are potent inhibitor bioactive compounds to Mpro PROTEIN and RdRp PROTEIN in comparison to antiviral drugs. Though, further in vitro and/or in vivo research is required to validate the docking results.

    Beclabuvir can Inhibit the RNA-dependent RNA Polymerase PROTEIN of Newly Emerged Novel Coronavirus (SARS-CoV-2)

    Authors: Kunal Dutta; Sergey Shityakov; Olga Morozova; Ibrahim Khalifa; Jin Zhang; Wei Zhu; Amiya Panda

    id:10.20944/preprints202003.0395.v2 Date: 2020-04-02 Source: Preprints.org

    Recent emergence of novel coronavirus (SARS-CoV-2) all over the world has resulted more than 33,106 global deaths. To date well-established therapeutics modules for infected MESHD patients are unknown. In this present initiative, molecular interactions between FDA-approved antiviral drugs against the Hepatitis-C virus MESHD ( HCV MESHD) have been investigated theoretically against the RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) of SARS-CoV-2. HCV MESHD and SARS-CoV-2 are both +ssRNA viruses. At 25o C beclabuvir, a non-nucleoside inhibitor of the RdRpHCV can efficiently bind to RdRp SARS-CoV-2 MESHD RdRp SARS-CoV-2 PROTEIN (ΔGAutoDock = -9.95 kcal mol-1) with an inhibition constant of 51.03 nM. Both the ΔGLondon and ΔGGBVI / WSA values were - 9.06 and - 6.67 kcal mol-1, respectively for binding of beclabuvir to RdRpSARS-CoV-2. In addition, beclabuvir has also shown better binding free energy with RdRpSARS-CoV-2 (ΔGvina = -8.0 kcal mol-1) than that observed with the Thumb 1 domain of RdRpHCV (ΔGvina = -7.1 kcal mol-1). InterProScan has suggested the RNA-directed 5'-3' polymerase activity exists within 549th to 776th amino acid residues of RdRpSARS-CoV, where the major amino acid residues interacting being I591, Y621, C624, D625, A690, N693, L760, D762, D763, and E813-N817. Molecular interaction suggests occupancy of beclabuvir inside the active site environment of the RdRpSARS-CoV-2, the enzyme essential for viral RNA synthesis. In conclusion, results suggest beclabuvir may serve as an anti-SARS-CoV-2 drug.

    Coronavirus SARS-CoV-2: Analysis of subgenomic mRNA transcription, 3CLpro PROTEIN and PL2pro protease cleavage sites and protein synthesis

    Authors: Miguel Ramos Pascual

    id:2004.00746v1 Date: 2020-04-02 Source: arXiv

    Coronaviruses have recently caused world-wide severe outbreaks: SARS ( Severe Acute Respiratory Syndrome MESHD) in 2002 and MERS MESHD ( Middle-East Respiratory Syndrome MESHD) in 2012. At the end of 2019, a new coronavirus outbreak appeared in Wuhan (China) seafood market as first focus of infection, becoming a pandemics in 2020, spreading mainly into Europe and Asia. Although the virus family is well-known, this specific virus presents considerable differences, as higher transmission rates, being a challenge for diagnostic methods, treatments and vaccines. Coronavirus(C++).pro is a C++ application which simulates Coronavirus replication cycle. This software has identified virus type in short times and provided FASTA files of virus proteins, a list of mRNA sequences and secondary structures. Furthermore, the software has identified a list of structural, non-structural and accessory proteins in 2019-nCoV virus genome more similar to SARS than to MERS MESHD, as several fusion proteins characteristics of this virus type. These results are useful as a first step in order to develop diagnostic methods, new vaccines or antiviral drugs, which could avoid virus replication in any stage: fusion inhibitors, RdRp PROTEIN inhibitors and PL2pro/ 3CLpro PROTEIN protease inhibitors.

    Analytical sensitivity and efficiency comparisons of SARS-COV-2 qRT-PCR assays

    Authors: Chantal B.F. Vogels; Anderson F. Brito; Anne Louise Wyllie; Joseph R Fauver; Isabel M. Ott; Chaney C. Kalinich; Mary E. Petrone; Arnau Casanovas-Massana; M. Catherine Muenker; Adam J. Moore; Jonathan Klein; Peiwen Lu; Alice Lu-Culligan; Xiaodong Jiang; Daniel J. Kim; Eriko Kudo; Tianyang Mao; Miyu Moriyama; Ji Eun Oh; Annsea Park; Julio Silva; Eric Song; Takehiro Takehashi; Manabu Taura; Maria Tokuyama; Arvind Venkataraman; Orr-El Weizman; Patrick Wong; Yexin Yang; Nagarjuna R. Cheemarla; Elizabeth White; Sarah Lapidus; Rebecca Earnest; Bertie Geng; Pavithra Vijayakumar; Camila Odio; John Fournier; Santos Bermejo; Shelli Farhadian; Charles Dela Cruz; Akiko Iwasaki; Albert I. Ko; Marie-Louise Landry; Ellen F. Foxman; Nathan D. Grubaugh

    doi:10.1101/2020.03.30.20048108 Date: 2020-04-01 Source: medRxiv

    The recent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exemplifies the critical need for accurate and rapid diagnostic assays to prompt clinical and public health interventions. Currently, several quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays are being used by clinical, research, and public health laboratories. However, it is currently unclear if results from different tests are comparable. Our goal was to evaluate the primer-probe sets used in four common diagnostic assays available on the World Health Organization (WHO) website. To facilitate this effort, we generated RNA transcripts to be used as assay standards and distributed them to other laboratories for internal validation. We then used (1) RNA transcript standards, (2) full-length SARS-CoV-2 RNA, (3) pre- COVID-19 MESHD nasopharyngeal swabs, and (4) clinical samples from COVID-19 MESHD patients to determine analytical efficiency and sensitivity of the qRT-PCR primer-probe sets. We show that all primer-probe sets can be used to detect SARS-CoV-2 at 500 virus copies per reaction, except for the RdRp PROTEIN-SARSr (Charite) confirmatory primer-probe set which has low sensitivity. Our findings characterize the limitations of currently used primer-probe sets and can assist other laboratories in selecting appropriate assays for the detection of SARS-CoV-2.

    Revealing Anti-viral Potential of Bio-active Therapeutics Targeting SARS-CoV2- polymerase ( RdRp PROTEIN) in Combating COVID-19 MESHD: Molecular Investigation on Indian Traditional Medicines

    Authors: Dhanasekaran Sivaraman; Puspharaj selvadoss Pradeep

    id:10.20944/preprints202003.0450.v1 Date: 2020-03-31 Source: Preprints.org

    Spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2 MESHD) made a historic transition between December 2019 to March 2020. In the present scenario SARS-CoV-2 as becomes a major burden on public health and economic stability of societies around the globe. From the substantial evidences gained from the pandemic of SARS-CoV-2 and MERS-CoV (Middle East respiratory syndrome coronavirus MESHD), scientists and clinicians strongly believes that these pathogenic viruses share common homology of some biologically active enzymes which includes RNA-dependent RNA polymerase PROTEIN ( RdRP PROTEIN), 3-chymotrypsin-like protease ( 3CLpro PROTEIN), papain-like protease PROTEIN ( PLpro PROTEIN) etc. RdRP PROTEIN relatively grabs higher level of clinical importance in comparison with other enzyme target. Indian system of traditional medicine pioneering the therapy towards infectious disease since several centuries. In view of this potential therapeutic leads from some of the Indian medicines along with standard drug favipiravir subjected to docking investigation targeting SARS-CoV-2- RNA dependent RNA polymerase PROTEIN ( RdRp PROTEIN). Residual proximity analysis reveals 18 out of 28 compounds reveals potential binding affinity of about 100% with the target amino acid residue (618 ASP, 760 ASP,761 ASP), 7 out of 28 reveals 75% binding efficacy and 3 out of 28 reveals 25% binding efficacy with that of the target residue. Hence further clinical validation may be warranted with proper in-vitro and in-vivo studies prior to the clinical recommendation in treating COVID-19 MESHD patient’s.

    Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase PROTEIN variant

    Authors: Maria Pachetti; Bruna Marini; Francesca Benedetti; Fabiola Giudici; Elisabetta Mauro; Paola Storici; Claudio Masciovecchio; Silvia Angeletti; Massimo Ciccozzi; Robert Charles Gallo; Davide Zella; Rudy Ippodrino

    doi:10.21203/rs.3.rs-20304/v1 Date: 2020-03-30 Source: ResearchSquare

    Background. SARS-CoV-2 is a RNA coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome MESHD ( COVID-19 MESHD). RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Virus mutagenic capability depends upon several factors, including the fidelity of viral enzymes that replicate nucleic acids, as SARS-CoV-2 RNA dependent RNA Polymerase PROTEIN ( RdRp PROTEIN). Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance. Methods. We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020. SARS-CoV-2 reference genome was obtained from the GenBank database. Genomes alignment was performed using Clustal Omega. Mann-Whitney and Fisher-Exact tests were used to assess statistical significance.Results. We characterized 8 novel recurrent mutations of SARS-CoV-2, located at positions 1397, 2891, 14408, 17746, 17857, 18060, 23403 and 28881. Mutations in 2891, 3036, 14408, 23403 and 28881 positions are predominantly observed in Europe, whereas those located at positions 17746, 17857 and 18060 are exclusively present in North America. We noticed that the 14408 mutation,  emerged for the first time in Europe in mid-February 2020, is present in the SARS-CoV-2 RdRp PROTEIN gene sequence. Viruses with RdRp PROTEIN mutation have a median of 3 point mutations [range: 2-5], otherwise they have a median of 1 mutation [range: 0-3] (p value < 0.001). Conclusions. These findings suggest that the virus is evolving and European, North American and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp PROTEIN to this phenomenon needs to be investigated. To date, several drugs targeting RdRp PROTEIN enzymes are being employed for SARS-CoV-2 infection MESHD treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft MESHD RdRp PROTEIN hydrophobic cleft, which is adjacent to the 14408 mutation we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp PROTEIN mutation in order to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates. 

    Comparative Genomic Analysis of Rapidly Evolving SARS CoV-2 Viruses Reveal Mosaic Pattern of Phylogeographical Distribution

    Authors: Roshan Kumar; Helianthous Verma; Nirjara Singhvi; Utkarsh Sood; Vipin Gupta; Mona Singh; Rashmi Sharma; Princy Hira; Shekhar Nagar; Chandni Talwar; Namita Nayyar; Shailly Anand; Charu Dogra Rawat; Mansi Verma; Ram Kishan Negi; Yogendra Singh; Rup Lal

    doi:10.1101/2020.03.25.006213 Date: 2020-03-30 Source: bioRxiv

    The Coronavirus Disease-2019 ( COVID-19 MESHD) that started in Wuhan, China in December 2019 has spread worldwide emerging as a global pandemic. The severe respiratory pneumonia MESHD caused by the novel SARS-CoV-2 has so far claimed more than 60,000 lives and has impacted human lives worldwide. However, as the novel SARS-CoV-2 displays high transmission rates, their underlying genomic severity is required to be fully understood. We studied the complete genomes of 95 SARS-CoV-2 strains from different geographical regions worldwide to uncover the pattern of the spread of the virus. We show that there is no direct transmission pattern of the virus among neighboring countries suggesting that the outbreak is a result of travel of infected humans to different countries. We revealed unique single nucleotide polymorphisms (SNPs) in nsp13-16 (ORF1b polyprotein) and S-Protein PROTEIN within 10 viral isolates from the USA. These viral proteins are involved in RNA replication, indicating highly evolved viral strains circulating in the population of USA than other countries. Furthermore, we found an amino acid addition in nsp16 (mRNA cap-1 methyltransferase) of the USA isolate (MT188341) leading to shift in amino acid frame from position 2540 onwards. Through the construction of SARS-CoV-2-human interactome, we further revealed that multiple host proteins (PHB, PPP1CA HGNC, TGF-{beta} HGNC, SOCS3 HGNC, STAT3 HGNC, JAK1/2, SMAD3 HGNC, BCL2 HGNC, CAV1 HGNC & SPECC1 HGNC) are manipulated by the viral proteins ( nsp2 HGNC, PL-PRO, N-protein PROTEIN, ORF7a PROTEIN, M-S- ORF3a PROTEIN complex, nsp7-nsp8-nsp9- RdRp complex PROTEIN) for mediating host immune evasion. Thus, the replicative machinery of SARS-CoV-2 is fast evolving to evade host challenges which need to be considered for developing effective treatment strategies.

    Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase PROTEIN Activity of nsp12 from the SARS-CoV-2 Virus

    Authors: Naveen Narayanan; Deepak T. Nair

    id:10.20944/preprints202003.0347.v1 Date: 2020-03-23 Source: Preprints.org

    SARS-CoV-2 is the causative agent for the ongoing COVID19 MESHD pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase PROTEIN ( RdRP PROTEIN) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP PROTEIN activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.

    Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase

    Authors: Minchen Chien; Thomas K. Anderson; Steffen Jockusch; Chuanjuan Tao; Shiv Kumar; Xiaoxu Li; James J. Russo; Robert Kirchdoerfer; Jingyue Ju

    doi:10.1101/2020.03.18.997585 Date: 2020-03-20 Source: bioRxiv

    SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 MESHD COVID-19 MESHD pandemic. Based on our analysis of hepatitis C virus MESHD and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C MESHD drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp MESHD RdRp PROTEIN, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/ AIDS MESHD drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B MESHD) for evaluation as inhibitors of SARS-CoV-2 RdRp MESHD RdRp PROTEIN. We demonstrated the ability of these three viral polymerase inhibitors, 3-fluoro-3-deoxythymidine triphosphate, 3-azido-3-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp PROTEIN, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19 MESHD.

    Binding Mechanism of Remdesivir to SARS-CoV-2 RNA Dependent RNA Polymerase PROTEIN

    Authors: Leili Zhang; Ruhong Zhou

    id:10.20944/preprints202003.0267.v1 Date: 2020-03-17 Source: Preprints.org

    Starting from December 2019, coronavirus disease 2019 MESHD ( COVID-19 MESHD) has emerged as a once-in-a-century pandemic with deadly consequences, which urgently calls for new treatments, cures and supporting apparatuses. Remdesivir was reported by World Health Organization (WHO) as the most promising drug currently available for the treatment of COVID-19 MESHD. Here, we use molecular dynamics simulations and free energy perturbation methods to study the inhibition mechanism of remdesivir to its target SARS-CoV-2 virus RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN). In the absence of a crystal structure of the SARS-CoV-2 RdRp PROTEIN, we first construct the homology model of this polymerase based on a previously available structure of SARS-CoV NSP12 RdRp MESHD NSP12 PROTEIN RdRp PROTEIN (with a sequence identify of 95.8%). We then build the putative binding mode by aligning the remdesivir + RdRp complex PROTEIN to the ATP bound poliovirus RdRp PROTEIN. The putative binding structure is further optimized with molecular dynamics simulations and demonstrated to be stable, indicating a reasonable binding mode for remdesivir. The relative binding free energy of remdesivir is calculated to be -8.28 ± 0.65 kcal/mol, much stronger than the natural substrate ATP (-4.14 ± 0.89 kcal/mol) which is needed for the polymerization. The ~800-fold improvement in the Kd from remdesivir over ATP indicates an effective replacement of APT in blocking of the RdRp PROTEIN binding pocket. Key residues D618, S549 and R555 are found to be the contributors to the binding affinity of remdesivir. These findings demonstrate that remdesivir can potentially act as a SARS-CoV-2 RNA-chain terminator, effectively stopping its RNA reproduction, with key residues also identified for future lead optimization and/or drug resistance studies.

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