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    Drug Repurposing against SARS-CoV-2 RDRP PROTEIN - a computational quest against CoVID- 19

    Authors: Hirak Jyoti Chakrabortya; Prasenjit Paria; Aditi Gangopadhyay; Sayak Ganguli

    doi:10.21203/rs.3.rs-22079/v1 Date: 2020-04-08 Source: ResearchSquare

    The present CoVID-19 MESHD CoVID-19 MESHD pandemic was first detected in December 2019 in Wuhan, China, and is rapidly spreading worldwide. To date, it has affected 465,915 individuals in 200 countries, and has been responsible for 21,031 deaths. In the absence of definitive treatment strategies, there is a pressing demand for drug discovery against CoVID-19 MESHD. Drug repurposing is a cost- effective and time-saving strategy which essentially involves the identification of novel targets for known drug candidates. This reduces the time and cost of drug discovery, as the pharmacokinetics and toxicity MESHD profiles of the drugs are already known, which makes phase-I clinical trials redundant. Here, we employed a computational drug repurposing strategy for identifying drug hits against the RNA-dependent RNA polymerase PROTEIN ( RDRP PROTEIN) protein of CoVID-19 MESHD. Analysis of the human-virus protein-protein associations revealed that the viral RDRP PROTEIN ( NSP12 PROTEIN) is associated with multiple host proteins that partake in cellular processes, which indicated that NSP12 PROTEIN could be a potential target for drug discovery. This, combined with the fact that the RDRP PROTEIN protein is a potential antiviral target in several viral diseases, led us to consider the NSP12 PROTEIN as a potential drug target for CoVID-19 MESHD. Owing to the absence of an experimentally-derived structure in the PDB, we constructed the NSP12 PROTEIN protein of CoVID-19 MESHD by homology modelling, and the potential druggable sites were analysed. The 13,533 entries in DrugBank were initially screened using the sequence of CoVID-19 MESHD NSP12 PROTEIN. The 7 hits thus identified were subjected to a consensus docking and scoring strategy for identifying hits against the druggable site of CoVID-19 MESHD NSP12 PROTEIN. Analysis of the docking scores and protein- ligand interactions revealed that two hits – N-alpha-[(benzyloxy)carbonyl]-n-[(1r)-4- hydroxy-1-methyl-2-oxobutyl]-l-phenylalaninamide and S-[5-(trifluoromethyl)-4h-1,2,4- triazol-3-yl] 5-(phenylethynyl) furan-2 -carbothioate, had stronger binding affinity than remdesivir, which is being presently tested in clinical trials for its antiviral activity against CoVID-19 MESHD. This indicated that these two compounds might be effective against CoVID-19 MESHD, however, further experimentation is necessary for obtaining substantial evidence. We believe that the results of this study could offer a novel avenue for drug development against CoVID- 19.

    Coevolution of Coronavirus and Paramyxovirus with Their Bat Hosts in the Same Geographical Areas

    Authors: Jie Liang; Chunchao Zhu; Libiao Zhang

    doi:10.21203/rs.3.rs-21963/v2 Date: 2020-04-08 Source: ResearchSquare

    Background: Bat-borne viruses are relatively host specific. In this study, we investigated the coevolution of coronavirus and paramyxovirus with their bat hosts. Published nucleotide sequences of the RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN) gene of 60 coronaviruses isolated from 37 bat species, the RNA polymerase large (L) gene of 36 paramyxoviruses isolated from 29 bat species, and the cytochrome B HGNC ( cytB HGNC) gene of 35 bat species were analyzed for coevolution signals. Each coevolution signal detected was tested and verified by the ParaFit and PACo functions in the R program. Results: Significant coevolution signals were detected in coronaviruses and paramyxoviruses and their bat hosts, and closely related bat hosts were found to carry closely related viruses. Conclusions: Our results suggest that similar geographical distribution and close phylogenetic relationship are requisites for inter-species transmission of viruses. 

    Does Zinc Supplementation Enhance the Clinical Efficacy of Chloroquine/Hydroxychloroquine to Win Todays Battle Against COVID-19 MESHD?

    Authors: Martin Scholz; Roland Derwand

    id:10.20944/preprints202004.0124.v1 Date: 2020-04-08 Source: Preprints.org

    Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 MESHD patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase PROTEIN activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease MESHD, chronic pulmonary disease MESHD, or diabetes MESHD, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 MESHD morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 MESHD clinical trials.

    Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

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

    doi:10.1101/2020.04.03.022939 Date: 2020-04-05 Source: bioRxiv

    SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 MESHD COVID-19 MESHD pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp PROTEIN catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19 MESHD.

    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. 

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