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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP15 (15)

ProteinS (7)

ComplexRdRp (5)

NSP3 (5)

NSP5 (4)


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SARS-CoV-2 Proteins
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    How the replication and transcription complex of SARS-CoV-2 functions in leader-to-body fusion

    Authors: Xin Li; Qiang Zhao; Jia Chang; Guangyou Duan; Jinlong Bei; Tung On Yau; Jianyi Yang; Jishou Ruan; Bingjun He; Gao Shan

    doi:10.1101/2021.02.17.431652 Date: 2021-02-17 Source: bioRxiv

    Background: Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2). Although unprecedented efforts are underway to develop therapeutic strategies against this disease, scientists have acquired only a little knowledge regarding the structures and functions of the CoV replication and transcription complex (RTC) and 16 non-structural proteins, named NSP1 HGNC-16. Results: In the present study, we determined the theoretical arrangement of NSP12 PROTEIN-16 in the global RTC structure. This arrangement answered how the CoV RTC functions in the "leader-to-body fusion" process. More importantly, our results revealed the associations between multiple functions of the RTC, including RNA synthesis, NSP15 PROTEIN cleavage, RNA methylation, and CoV replication and transcription at the molecular level. As the most important finding, transcription regulatory sequence (TRS) hairpins were reported for the first time to help understand the multiple functions of CoV RTCs and the strong recombination abilities of CoVs. Conclusions: TRS hairpins can be used to identify recombination regions in CoV genomes. We provide a systematic understanding of the structures and functions of the RTC, leading to the eventual determination of the global CoV RTC structure. Our findings enrich fundamental knowledge in the field of gene expression and its regulation, providing a basis for future studies. Future drug design targeting SARS-CoV-2 needs to consider protein-protein and protein-RNA interactions in the RTC, particularly the complex structure of NSP15 PROTEIN and NSP16 PROTEIN with the TRS hairpin.

    High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity.

    Authors: Ryan Choi; Mowei Zhou; Roger Shek; Jesse W Wilson; Logan Tillery; Justin K Craig; Indraneel A Salukhe; Sarah E Hickson; Neeraj Kumar; Rhema M James; Garry W Buchko; Ruilian Wu; Sydney Huff; Tu-Trinh Nguyen; Brett L Hurst; Sara Cherry; Lynn K Barrett; Wesley C Van Voorhis; Amr Jamal; Ali M Somily

    doi:10.1101/2021.01.21.427657 Date: 2021-01-21 Source: bioRxiv

    SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19 MESHD. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease PROTEIN ( endoU HGNC) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU HGNC inhibitors in the 1-20 uM range in vitro. Furthermore, Exebryl-1, a beta-amyloid anti-aggregation molecule for Alzheimers MESHD therapy, was shown to have antiviral activity between 10 to 66 uM, in VERO, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU HGNC inhibitor and as a SARS-CoV-2 antiviral.

    A COVID-19 MESHD Drug Repurposing Strategy Through Quantitative Homological Similarities by using a Topological Data Analysis Based Formalism

    Authors: Raul Pérez-Moraga; Jaume Forés-Martos; Beatriz Suay; Jean-Louis Duval; Antonio Falcó; Joan Climent

    id:10.20944/preprints202012.0281.v1 Date: 2020-12-11 Source: Preprints.org

    Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 65 million cases and one point five million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We created a novel computational pipeline aimed to speed up the process of repurposable candidate drug identification. Compared with current drug repurposing methodologies, our strategy is centered on filtering the best candidate among all selected targets focused on the introduction of a mathematical formalism motivated by recent advances in the fields of algebraic topology and topological data analysis (TDA). This formalism allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 PROTEIN endoribonuclease, and NSP12 PROTEIN RNA-dependent RNA polymerase PROTEIN), which included rutin, dexamethasone, and vemurafenib among others. To our knowledge, it is the first time that a TDA based strategy has been used to compare a massive amount of protein structures with the final objective of performing drug repurposing

    Generation of restriction endonucleases PROTEIN barcode map to trace SARS-CoV-2 origin and evolution.

    Authors: Federico Colombo; Elisa Corsiero; Myles J. Lewis; Costantino Pitzalis

    doi:10.21203/rs.3.rs-105132/v1 Date: 2020-11-09 Source: ResearchSquare

    Since the first report of SARS-CoV-2 in China in 2019, there has been a huge debate about the origin. In this work, using a different method we aimed to strengthen the observation that no evidence of genetic manipulation has been found by i) detecting classical restriction site ( RS MESHD) sequence in human SARS-CoV-2 genomes and ii) comparing them with other recombinant SARS-CoV MESHD-like virus created for experimental purposes. Finally, we propose a novel approach consisting in the generation of a restriction endonucleases PROTEIN site map of SARS-CoV-2 and other related coronavirus genomes to be used as a fingerprint to trace the virus evolution.

    One-tube SARS-CoV-2 detection platform based on RT-RPA and CRISPR/Cas12a

    Authors: Yangyang Sun; Lei Yu; Chengxi Liu; Shanting Ye; Wei Chen; Dechang Li; Weiren Huang

    doi:10.21203/rs.3.rs-96229/v2 Date: 2020-10-21 Source: ResearchSquare

    Background: COVID-19 MESHD has spread rapidly around the world, affecting a large percentage of the population. When lifting certain mandatory measures for an economic restart, robust surveillance must be established and implemented, with nucleic acid detection for SARS-CoV-2 as an essential component. Methods: We tried to develop a one-tube detection platform based on RT-RPA (Reverse Transcription and Recombinase Polymerase Isothermal Amplification) and DNA Endonuclease PROTEIN-Targeted CRISPR Trans Reporter (DETECTR) technology, termed OR-DETECTR, to detect SARS-CoV-2. We designed RT-RPA primers of the RdRp PROTEIN and N genes PROTEIN following the SARS-CoV-2 gene sequence. We optimized reaction components so that the detection process could be carried out in one tube. Specificity was demonstrated by detecting nucleic acid samples from pseudoviruses from seven human coronaviruses and Influenza A (H1N1). Clinical samples were used to validate the platform and all results were compared to rRT-PCR. RNA standards and pseudoviruses diluted by different gradients were used to demonstrate the detection limit. Additionally, we have developed a lateral flow assay based on OR-DETECTR for detecting COVID-19 MESHD.Results: The OR-DETECTR detection process can be completed in one tube, which takes approximately 50 min. This method can specifically detect SARS-CoV-2 from seven human coronaviruses and Influenza A (H1N1), with a low detection limit of 2.5 copies/µl input (RNA standard) and 1 copy/µl input (pseudovirus). Results of six samples from SARS-CoV-2 patients, eight samples from patients with fever MESHD but no SARS-CoV-2 infection MESHD, and one mixed sample from 40 negative controls showed that OR-DETECTR is 100% consistent with rRT-PCR. The lateral flow assay based on OR-DETECTR can be used for the detection of COVID-19 MESHD, and the detection limit is 2.5 copies/µl input.Conclusions: The OR-DETECTR platform for the detection of COVID-19 MESHD is rapid, accurate, tube closed, easy-to-operate, and free of large instruments.

    A Systemic and Molecular Study of Subcellular Localization of SARS-CoV-2 Proteins

    Authors: Jing Zhang; Ruth Cruz-cosme; Meng-Wei Zhuang; Dongxiao Liu; Yuan Liu; Shaolei Teng; Pei-Hui Wang; Qiyi Tang

    doi:10.1101/2020.08.02.233023 Date: 2020-08-02 Source: bioRxiv

    Coronavirus possesses the largest RNA genome among all the RNA viruses. Its genome encodes about 29 proteins. Most of the viral proteins are non-structural proteins (NSP) except envelop (E), membrane (M), nucleocapsid (N PROTEIN) and Spike (S) proteins PROTEIN that constitute the viral nucleocapsid, envelop and surface. We have recently cloned all the 29 SARS-CoV-2 genes into vectors for their expressions in mammalian cells except NSP11 PROTEIN that has only 14 amino acids (aa). We are able to express all the 28 cloned SARS-CoV-2 genes in human cells to characterize their subcellular distributions. The proteins of SARS-CoV-2 are mostly cytoplasmic but some are both cytoplasmic and nuclear. Those punctate staining proteins were further investigated by immunofluorescent assay (IFA) using specific antibodies or by co-transfection with an organelle marker-expressing plasmid. As a result, we found that NSP15 PROTEIN, ORF6 PROTEIN, M and ORF7a PROTEIN are related to Golgi apparatus, and that ORF7b PROTEIN, ORF8 PROTEIN and ORF10 PROTEIN colocalize with endoplasmic reticulum (ER). Interestingly, ORF3a PROTEIN distributes in cell membrane, early endosome, endosome, late endosome and lysosome, which suggests that ORF3a PROTEIN might help the infected virus to usurp endosome and lysosome for viral use. Furthermore, we revealed that NSP13 PROTEIN colocalized with SC35 HGNC, a protein standing for splicing compartments in the nucleus. Our studies for the first time visualized the subcellular locations of SARS-CoV-2 proteins MESHD and might provide novel insights into the viral proteins biological functions.

    A Combination of Ivermectin and Doxycycline Possibly Blocks the Viral Entry and Modulate the Innate Immune Response in COVID-19 MESHD Patients

    Authors: Dharmendra Kumar Maurya

    doi:10.26434/chemrxiv.12630539.v1 Date: 2020-07-09 Source: ChemRxiv

    The current outbreak of the corona virus disease 2019 ( COVID-19 MESHD), has affected almost entire world and become pandemic now. Currently, there is neither any FDA approved drugs nor any vaccines available to control it. Very recently in Bangladesh, a group of doctors reported astounding success in treating patients suffering from COVID-19 MESHD with two commonly used drugs, Ivermectin and Doxycycline. In the current study we have explored the possible mechanism by which these drugs might have worked for the positive response in the COVID-19 MESHD patients. To explore the mechanism we have used molecular docking and molecular dynamics simulation approach. Effectiveness of Ivermectin and doxycycline were evaluated against Main Protease PROTEIN ( Mpro PROTEIN), Spike (S) protein PROTEIN, Nucleocapsid (N PROTEIN), RNA-dependent RNA polymerase PROTEIN ( RdRp PROTEIN, NSP12 PROTEIN), ADP Ribose Phosphatase ( NSP3 HGNC NSP3 PROTEIN), Endoribonuclease ( NSP15 PROTEIN) and methyltransferase ( NSP10 PROTEIN- NSP16 PROTEIN complex) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) receptor. Our study shows that both Ivermectin and doxycycline have significantly bind with SARS-CoV-2 proteins but Ivermectin was better binding than doxycycline. Ivermectin showed a perfect binding site to the Spike-RBD and ACE2 HGNC interacting region indicating that it might be interfering in the interaction of spike with ACE2 HGNC and preventing the viral entry in to the host cells. Ivermectin also exhibited significant binding affinity with different SARS-CoV-2 structural and non-structural proteins (NSPs) which have diverse functions in virus life cycle. Significant binding of Ivermectin with RdRp PROTEIN indicate its role in the inhibition of the viral replication and ultimately impeding the multiplication of the virus. Ivermectin also possess significant binding affinity with NSP3 HGNC NSP3 PROTEIN, NSP10 PROTEIN, NSP15 PROTEIN and NSP16 PROTEIN which helps virus in escaping from host immune system. Molecular dynamics simulation study shows that binding of the Ivermectin with Mpro PROTEIN, Spike, NSP3 HGNC NSP3 PROTEIN, NSP16 PROTEIN and ACE2 HGNC was quiet stable. Thus, our docking and simulation studies reveal that combination of Ivermectin and doxycycline might be executing the effect by inhibition of viral entry and enhance viral load clearance by targeting various viral functional proteins.

    Identification of promising drug candidates against Non-Structural Protein 15 PROTEIN ( NSP15 PROTEIN) from SARS-CoV-2: an in silico assisted drug-repurposing studies

    Authors: Rameez Jabeer Khan; Rajat Kumar Jha; Ekampreet Singh; Monika Jain; Gizachew Muluneh Amera; Rashmi Prabha Singh; Jayaraman Muthukumaran; Amit Kumar Singh

    doi:10.26434/chemrxiv.12407711.v1 Date: 2020-06-03 Source: ChemRxiv

    The recent COVID-19 MESHD COVID-19 MESHD pandemic caused by SARS-CoV-2 has recorded a high number of infected people MESHD across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 PROTEIN ( NSP15 PROTEIN), i.e. a uridylate specific endoribonuclease of SARS-CoV-2which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 PROTEIN was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (ΔG), estimated inhibition constant (Ki), the orientation of drug molecules in the active site and the key interacting residues ofNSP15. The MD simulations were performed for the selected NSP15 PROTEIN-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15 PROTEIN-drug complexes were also calculated using the trajectories of MD simulations of NSP15 PROTEIN-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15 PROTEIN-Simeprevir (-242.559 kJ/mol) and NSP15 PROTEIN-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 PROTEIN and could act as potential therapeutic agents against SARS-CoV-2.

    Shortlisting Phytochemicals Exhibiting Inhibitory Activity against Major Proteins of SARS-CoV-2 through Virtual Screening

    Authors: Saranya Nallusamy; Jayakanthan Mannu; Caroline Ravikumar; Kandavelmani Angamuthu; Bharathi Nathan; Kumaravadivel Nachimuthu; Gnanam Ramasamy; Raveendran Muthurajan; Mohankumar Subbarayalu; Kumar Neelakandan

    doi:10.21203/rs.3.rs-31834/v1 Date: 2020-05-27 Source: ResearchSquare

    Severe Acute Respiratory Syndrome Corona Virus 2 MESHD (SARS-CoV-2) declared as a pandemic by WHO that has affected more than 40 lakh peoples and caused death MESHD of more than 2 lakh individuals across the globe. Limited availability of genomic information of SARS-CoV-2 and non-availability of vaccines and effective drugs are major problems responsible for the ineffective control and management of this pandemic. Several attempts have been made to explore repurposing existing drugs known for their anti-viral activities, and test the traditional herbal medicines known for their health benefiting and immune boosting activity against SARS-CoV-2.In this study, efforts were made to examine the potential of 721 phytochemicals of 37 plant species in inhibiting major protein targets namely, spike glycoprotein PROTEIN, main protease PROTEIN (MPro), NSP3 HGNC NSP3 PROTEIN, NSP9 PROTEIN, NSP15 PROTEIN, NSP10 PROTEIN- NSP16 PROTEIN and RNA dependent RNA polymerase PROTEIN of SARS-CoV-2 through virtual screening approach. Results of our experiments revealed that SARS-CoV-2 MPro shared significant dissimilarities against SARS-CoVMPro and MERS-CoVMPro indicating the need for discovering novel drugs. This study has identified the phytochemical cyanin (Zingiber officinale) exhibiting broad spectrum inhibitory activity against main proteases PROTEIN of all the three Coronaviruses. Amentoflavone, agathisflavone, catechin-7-o-gallate and chlorogeninwere shown to exhibit multi target inhibitory activity. This study has identified Mangifera indica, Anacardium occidentale, Vitex negundo, Solanum nigrum, Pedalium murex, Terminalia chebula, Azadirachta indica, Cissus quadrangularis, Clerodendrum serratum and Ocimum basilicum as potential sources of phytochemicals combating n COVID-19 MESHD. More interestingly, this study has generated evidences for the anti-viral properties of the traditional herbal formulation “Kabasura kudineer” recommended by AYUSH, a unit of Government of India. Testing of short listed phytochemicals through clinical trials will help in developing effective formulation for management of this pandemic disease. Genomic analysis of identified herbal plants will help in unravelling molecular complexity of therapeutic and anti-viral properties and will pave way for designing synthetic drugs. 

    Analysis of the full genome sequences of SARS-CoV-2 isolates to determine antigenic proteins and epitopes to be used for the development of a vaccine or a diagnostic approach for COVID-19 MESHD

    Authors: Hüseyin Can; Ahmet Efe Köseoğlu; Sedef Erkunt Alak; Mervenur Güvendi; Mert Döşkaya; Muhammet Karakavuk; Adnan Yüksel Gürüz; Cemal Ün

    doi:10.21203/rs.3.rs-28142/v1 Date: 2020-05-08 Source: ResearchSquare

    In genome of SARS-CoV-2, the 5’-terminus encodes a polyprotein (pp1ab), which is further cleaved into 15 non-structural proteins PROTEIN (nsp-1 to nsp-10 and nsp-12 to nsp-16) whereas the 3’ terminus encodes four structural proteins (spike PROTEIN, envelope, membrane, and nucleocapsid) and eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14). Among these 27 proteins, the present study aimed to discover likely antigenic proteins and epitopes to be used for during the development of a vaccine or serodiagnostic assay using a reverse vaccinology in silico approach. For this purpose, after the full genome analyses of SARS-CoV-2 isolates, viral surface proteins including spike, envelope and membrane proteins as well as proteins with predicted signal peptide were determined as probable vaccine candidates whereas the remaining were considered as possible antigens to be used during development of serodiagnostic assays. According to results, the phylogenetic analysis of SARS-CoV-2 isolates from 31 different countries showed two significant clusters in which one was clustered with China-Wuhan and the other one with China-Yunnan isolates. During the analyses, 105 SNPs were identified that resulted in change in 70 amino acid positions. Among the 27 proteins, 26 of them were predicted as probable antigen, except nsp-16. In 26 proteins, spike PROTEIN protein was selected as the best vaccine candidate because of having a signal peptide, negative grand average of hydropathicity value, one transmembrane helix, moderate aliphatic index, a big molecular weight, a long-estimated half-life, beta wrap motifs as well as having a stable, soluble and non-allergic features. In addition, orf7a PROTEIN, orf8 and nsp-10 proteins were considered as potential vaccine candidates because of having signal peptides. Nucleocapsid protein PROTEIN and a highly antigenic GGDGKMKD epitope of nucleocapsid protein PROTEIN were identified as ideal antigens to be used in development of serodiagnostic assays. Moreover, considering MHC-I alleles, highly antigenic KLNDLCFTNV and ITLCFTLKRK epitopes belonging to spike and orf7a PROTEIN proteins can be used to develop an epitope-based peptide vaccine or used as antigen for development of serodiagnostic assay.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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