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    DNA-Directed Patterning for Versatile Validation and Characterization of a Lipid-Based Nanoparticle Model of SARS-CoV-2

    Authors: Molly Kozminsky; Thomas Carey; Lydia L. Sohn

    doi:10.26434/chemrxiv.14208455.v1 Date: 2021-03-16 Source: ChemRxiv

    Lipid-based nanoparticles have risen to the forefront of the COVID-19 pandemic MESHD—from encapsulation of vaccine components to modeling the virus, itself. Their rapid development in the face of the volatile nature of the pandemic requires high-throughput, highly flexible methods for characterization. DNA-directed patterning is a versatile method to immobilize and segregate lipid-based nanoparticles for subsequent analysis. DNA-directed patterning selectively conjugates oligonucleotides onto a glass substrate and then hybridizes them to complementary oligonucleotides tagged to the liposomes, thereby patterning them with great control and precision. The power of this method is demonstrated by characterizing a novel recapitulative lipid-based nanoparticle model of SARS-CoV-2 —S-liposomes— which present the SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN on their surfaces. Patterning of a mixture of S-liposomes and liposomes that display the tetraspanin CD63 HGNC into discrete regions of a substrate is used to show that ACE2 HGNC specifically binds to S-liposomes. Importantly, DNA-directed patterning of S-liposomes is used to verify the performance of a commercially available neutralizing antibody against the S protein PROTEIN S protein HGNC. Ultimately, the introduction of S-liposomes to ACE2 HGNC-expressing cells demonstrates the biological relevance of DNA-directed patterning. Overall, DNA-directed patterning enables a wide variety of custom assays for the characterization of any lipid-based nanoparticle.

    SARS-CoV-2 comprehensive receptor profiling: mechanistic insight to drive new therapeutic strategies

    Authors: Sarah MV Brockbank; Raquel Faba-Rodriguez; Lyn Rosenbrier Ribeiro; Catherine Geh; Helen Thomas; Jenni Delight; Lucy Coverley; W Mark Abbott; Jo Soden; Jim Freeth

    doi:10.1101/2021.03.11.434937 Date: 2021-03-11 Source: bioRxiv

    Here we describe a hypothesis free approach to screen for interactions of SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN with human cell surface receptors. We used a library screening approach to detect binding interactions across one of the largest known panels of membrane-bound and soluble receptors, comprising 5845 targets, expressed recombinantly in human cells. We were able confirm and replicate SARS-CoV-2 binding to ACE2 HGNC and other putative coreceptors such as CD209 HGNC and CLEC4M HGNC. More significantly, we identified interactions with a number of novel SARS-CoV-2 S binding proteins. Three of these novel receptors, NID1 HGNC, CNTN1 HGNC and APOA4 HGNC were specific to SARS-CoV-2, and not SARS-COV MESHD, with APOA4 HGNC binding the S-protein HGNC S-protein PROTEIN with equal affinity as ACE2 HGNC. With this knowledge we may further understand the disease pathogenesis of COVID-19 MESHD patients and how infection by SARS-CoV-2 may lead to differences in pathology in specific organs or indeed the virulence observed in different ethnicities. Importantly we illustrate a methodology which can be used for rapid, unbiassed identification of cell surface receptors, to support drug screening and drug repurposing approaches for this and future pandemics.

    Molecular strategies for antibody binding and escape of SARS-CoV-2 and its mutations

    Authors: Mohamed Hendy; Samuel Kaufman; Mauricio Ponga

    doi:10.1101/2021.03.04.433970 Date: 2021-03-05 Source: bioRxiv

    The COVID19 MESHD pandemic, caused by SARS-CoV-2, has infected more than 100 million people worldwide. Due to the rapid spreading of SARS-CoV-2 and its impact, it is paramount to find effective treatments against it. Human neutralizing antibodies are an effective method to fight viral infection MESHD. However, the recent discovery of new strains that substantially change the S-protein HGNC S-protein PROTEIN sequence has raised concern about vaccines and antibodies' effectiveness. Here, we investigated the binding mechanisms between the S-protein HGNC S-protein PROTEIN and several antibodies. Multiple mutations were included to understand the strategies for antibody escape in new variants. We found that the combination of mutations K417N and E484K produced higher binding energy to ACE2 HGNC than the wild type, suggesting higher efficiency to enter host cells. The mutations' effect depends on the antibody class. While Class I enhances the binding avidity in the presence of N501Y mutation, class II antibodies showed a sharp decline in the binding affinity. Our simulations suggest that Class I antibodies will remain effective against the new strains. In contrast, Class II antibodies will have less affinity to the S-protein HGNC S-protein PROTEIN, potentially affecting these antibodies' efficiency.

    Intermolecular Interaction Analyses on SARS-CoV-2 Receptor Binding Domain and Human Angiotensin-Converting Enzyme 2 HGNC Receptor-Blocking Antibody/peptide Using Fragment Molecular Orbital Calculation

    Authors: Kazuki Watanabe; Chiduru Watanabe; Teruki Honma; Yu-Shi Tian; Yusuke Kawashima; Norihito Kawashita; Tatsuya Takagi; Kaori Fukuzawa

    doi:10.26434/chemrxiv.14135138.v1 Date: 2021-03-02 Source: ChemRxiv

    The spike glycoprotein PROTEIN ( S-protein PROTEIN S-protein HGNC) mediates SARS-CoV-2 entry via intermolecular interaction with human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC). The receptor-binding domain (RBD) of the S-protein HGNC S-protein PROTEIN has been considered critical for this interaction and acts as the target of numerous neutralizing antibodies and antiviral peptides. This study used the fragment molecular orbital (FMO) method to analyze the interactions between RBD and antibodies/peptides and extracted crucial residues that can be used to epitopes. The interactions evaluated as inter-fragment interaction energy (IFIE) values between the RBD and 12 antibodies/peptides showed a fairly good correlation with the experimental activity pIC50 (R2 = 0.540). Nine residues (T415, K417, Y421, F456, A475, F486, N487, N501, and Y505) were confirmed as crucial. Pair interaction energy decomposition analyses (PIEDA) showed that hydrogen bonds, electrostatic interactions, and π-orbital interactions are important. Our results provide essential information for understanding SARS-CoV-2-antibodies/peptide binding and may play roles in future antibody/antiviral drug design.

    Newborn antibodies to SARS-CoV-2 detected in cord blood after maternal vaccination

    Authors: Paul D Gilbert; Chad A Rudnick

    doi:10.1101/2021.02.03.21250579 Date: 2021-02-05 Source: medRxiv

    Background: Maternal vaccination for Influenza and TDaP have been well studied in terms of safety and efficacy for protection of the newborn by placental passage of antibodies. Similar newborn protection would be expected after maternal vaccination against SARS-CoV-2 (the virus responsible for COVID-19 MESHD). There is a significant and urgent need for research regarding safety and efficacy of vaccination against SARS-CoV-2 during pregnancy. Here, we report the first known case of an infant with SARS-CoV-2 IgG antibodies detectable in cord blood after maternal vaccination. Case presentation: A vigorous, healthy, full-term female was born to a COVID-19 MESHD naive mother who had received a single dose of mRNA vaccine for SARS-CoV-2 three weeks prior to delivery. Cord blood antibodies (IgG) were detected to the S-protein PROTEIN S-protein HGNC of SARS-CoV-2 at time of delivery. Conclusion: Here, we report the first known case of an infant with SARS-CoV-2 IgG antibodies detectable in cord blood after maternal vaccination.

    Molecular dynamics simulation study of effects of key mutations in SARS-CoV-2 on protein structures

    Authors: Jerome Rumdon Lon; Binbin Xi; Bingxu Zhong; Yiyuan Zheng; Pei Guo; Zixi Chen; Hongli Du

    doi:10.1101/2021.02.03.429495 Date: 2021-02-03 Source: bioRxiv

    SARS-CoV-2 has been spreading rapidly since 2019 and has produced large-scale mutations in the genomes. Differences in gene sequences may lead to changes in protein structure and traits, which would have a great impact on the epidemiological characteristics. In this study, we selected the key mutations of SARS-CoV-2, including D614G and A222V of S protein PROTEIN S protein HGNC and Q57H of ORF3a PROTEIN protein, to conduct molecular dynamics simulation and analysis on the structures of the mutant proteins. The results suggested that D614G improved the stability of S protein PROTEIN S protein HGNC, while A222V enhanced the ability of protein to react with the outside environment. Q57H enhanced the structural flexibility of ORF3a PROTEIN protein. Our findings could complete the mechanistic link between genotype--phenotype--epidemiological characteristics in the study of SARS-CoV-2. We also found no significant changes in the antigenicity of S protein HGNC S protein PROTEIN, ORF3a PROTEIN protein and their mutants, which provides reference for vaccine development and application.

    Statistical challenges in the analysis of sequence and structure data for the COVID-19 MESHD spike protein PROTEIN

    Authors: Shiyu He; Samuel W. K. Wong

    id:2101.02304v2 Date: 2021-01-06 Source: arXiv

    As the major target of many vaccines and neutralizing antibodies against SARS-CoV-2, the spike PROTEIN ( S) protein PROTEIN is observed to mutate over time. In this paper, we present statistical approaches to tackle some challenges associated with the analysis of S-protein HGNC S-protein PROTEIN data. We build a Bayesian hierarchical model to study the temporal and spatial evolution of S-protein HGNC S-protein PROTEIN sequences, after grouping the sequences into representative clusters. We then apply sampling methods to investigate possible changes to the S-protein HGNC S-protein PROTEIN's 3-D structure as a result of commonly observed mutations. While the increasing spread of D614G variants has been noted in other research, our results also show that the co-occurring mutations of D614G together with S477N or A222V may spread even more rapidly, as quantified by our model estimates.

    In-Vitro Fluorescence Microscopy Studies Show Retention of Spike-Protein PROTEIN (SARS-Cov-2) on Cell Membrane in the Presence of Amodiaquin Dihydrochloride Dihydrate Drug

    Authors: Partha Pratim Mondal; Subhra Mandal; Tien Huynh; Jessica A. Chichester; Reynette Estelien; Julio Sanmiguel; Kristofer T. Michalson; Cheikh Diop; Dawid Maciorowski; Wenbin Qi; Elissa Hudspeth; Allison Cucalon; Cecilia D. Dyer; M. Betina Pampena; James J. Knox; Regina C. LaRocque; Richelle C. Charles; Dan Li; Maya Kim; Abigail Sheridan; Nadia Storm; Rebecca I. Johnson; Jared Feldman; Blake M. Hauser; Aisling Ryan; Dione T. Kobayashi; Ruchi Chauhan; Marion McGlynn; Edward T. Ryan; Aaron G. Schmidt; Brian Price; Anna Honko; Anthony Griffiths; Sam Yaghmour; Robert Hodge; Michael R. Betts; Mason W. Freeman; James M. Wilson; Luk H. Vandenberghe

    doi:10.1101/2021.01.05.424956 Date: 2021-01-05 Source: bioRxiv

    The ability of S-glycoprotein PROTEIN ( S-protein PROTEIN S-protein HGNC) in SARS-Cov-2 to bind to the host cell receptor protein (angiotensinconverting enzyme 2 HGNC ( ACE2 HGNC)) leading to its entry in cellular system determines its contagious index and global spread. Three available drugs (Riboflavin, Amodiaquin dihydrochloride dihydrate ( ADD MESHD) and Remidesivir) were investigated to understand the kinetics of S-protein HGNC S-protein PROTEIN and its entry inside a cellular environment. Optical microscopy and fluorescence-based assays on 293T cells (transfected with ACE2 HGNC plasmid) were used as the preamble for assessing the behaviour of S-protein PROTEIN S-protein HGNC in the presence of these drugs for the first 12 hours post S-protein PROTEIN S-protein HGNC - ACE2 HGNC binding. Preliminary results suggest relatively long retention of S-protein PROTEIN S-protein HGNC on the cell membrane in the presence of ADD drug. Evident from the %-overlap and colocalization of S-protein HGNC S-protein PROTEIN with endosome studies, a large fraction of S-protein HGNC S-protein PROTEIN entering the cell escape endosomal degradation process, suggesting S-protein HGNC S-protein PROTEIN takes non-endocytic mediated entry in the presence of ADD MESHD, whereas in the presence of Riboflavin, S-protein HGNC S-protein PROTEIN carry out normal endocytic pathway, comparable to control (no drug) group. Therefore, present study indicates ADD potentially affects S-protein HGNC S-protein PROTEIN's entry mechanism (endocytic pathway) in addition to its reported target action mechanism. Hence, ADD substantially interfere with S-protein PROTEIN S-protein HGNC cellular entrance mechanism. However, further detailed studies at molecular scale will clarify our understanding of exact intermediate molecular processes. The present study (based on limited data) reveal ADD MESHD could be potential candidate to manage Covid-19 MESHD functions through yet unknown molecular mechanism.

    Bioactive Agents Contained in Different Nasal Sprays May Defeat SARS-Cov-2: A Repurposing and In-Silico Approach

    Authors: Mohammad Faheem Khan; Waseem Ahmad Ansari; Tanveer Ahamad; Mohsin Ali Khan; Zaw Ali Khan; Aqib Sarfraz; Mohd Aamish Khan

    doi:10.21203/rs.3.rs-135981/v1 Date: 2020-12-25 Source: ResearchSquare

    Recently, Coronavirus Disease 2019 MESHD ( COVID-19 MESHD), caused by fast-spreading and highly contagious severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2), has been declared as a pandemic disease of the 21st century by the World Health Organization (WHO). SARS-CoV-2 enters into the human respiratory system by binding of the viral surface spike glycoprotein PROTEIN ( S-protein PROTEIN S-protein HGNC) to angiotensin-converting enzyme2 HGNC ( ACE2 HGNC) receptor that is found in the nasal passage and oral cavity of a human. Both spike protein PROTEIN and the ACE2 HGNC receptor have been identified as promising therapeutic targets to develop anti-SARS-CoV-2 drugs. Although in the last few months, various studies have identified some promising molecules against both the receptors including human ACE2 HGNC and SARS-CoV-2 spike PROTEIN protein, still there is no vaccine or therapeutic drugs as of today. The repurposing of FDA-approved drugs may provide a rapid and potential treatment to combat COVID-19 MESHD by using high throughput virtual screening approach. In the present study, we have used the repurposing approach for bioactive agents of the nasal spray against human ACE2 HGNC and SARS-CoV-2 spike PROTEIN protein to identify the anti- COVID-19 MESHD agents with the help of molecular docking study. To this, we screened the sixteen bioactive agents of the nasal spray by analyzing their binding free energy and binding mode through molecular docking study. As a result, bioactive agents such as ciclesonide, levocabastine, and triamcinolone acetonide were found as highly active ligands with potent binding affinities against both the targets human ACE2 HGNC and SARS-CoV-2 spike PROTEIN proteins. Thus, these bioactive agents may effectively assist to control the COVID-19 MESHD by inhibiting the human ACE2 HGNC receptor as well as spike protein PROTEIN of SARS-CoV-2.

    Complete Protection of Nasal and Lung Airways Against SARS-CoV-2 Challenge by Antibody Plus Th1 HGNC Dominant N- and S-Specific T-Cell Responses to Subcutaneous Prime and Thermally-Stable Oral Boost Bivalent hAd5 Vaccination in an NHP Study

    Authors: Elizabeth Gabitzsch; Jeffrey T Safrit; Mohit Verma; Adrian Rice; Peter Sieling; Lise Zakin; Annie Shin; Brett Morimoto; Helty Adisetiyo; Raymond Wong; Ashish Bezawada; Kyle Dinkins; Joseph Balint; Victor Peykov; Hermes Garban; Philip Liu; Andrew Bacon; Jeff Drew; Patricia Spilman; Lennie Sender; Shahrooz Rabizadeh; Kayvan Niazi; Patrick Soon-Shiong

    doi:10.1101/2020.12.08.416297 Date: 2020-12-09 Source: bioRxiv

    BackgroundTo address the dire need for a safe and effective vaccine to protect individuals from and reduce transmission of SARS-CoV-2, we developed a COVID-19 MESHD vaccine that elicits not only robust humoral responses but also activates T cells. Our bivalent vaccine expresses both an optimized viral spike (S) protein PROTEIN S) protein HGNC (S-Fusion) and the viral nucleocapsid (N) protein PROTEIN with an Enhanced T-cell Stimulation Domain (N-ETSD) that directs N to the endo/lysosomal subcellular compartment to enhance MHC class II responses. The vaccine antigens are delivered by the second-generation adenovirus serotype 5 [E1-, E2b-, E3-] platform (hAd5) that has been safely administered and found to be effective in generating tumor MESHD-specific T cells even in the presence of pre-existing adenovirus immunity. Here, we report our findings on the safety and efficacy of our hAd5 S-Fusion + N-ETSD subcutaneous (SC) prime and thermally-stable oral boost vaccine in generating SARS-CoV-2-neutralizing antibodies, eliciting N- and S-specific T-cell responses, and providing complete protection with the clearing of virus after challenge in Non-Human Primates (NHP). A key objective of the study was to explore the efficacy of a novel thermally-stable oral hAd5 S-Fusion + N-ETSD to serve as a booster dose following an SC prime. MethodsGroup 1 NHP received the hAd5 S-Fusion + N-ETSD vaccine on Days 0 and 14 by SC injection (1011 VP), and on Day 28 by a single oral boost (1010 VP); Group 2 received vaccination on the same schedule, but with an SC prime and two oral boosts. Group 3 placebo NHP were dosed with vehicle-only SC-oral-oral. Blood for the isolation of sera and PBMCs was collected throughout the study. ELISA was used for determination of anti-S IgG levels, cPass for presence of neutralizing antibodies, and ELISpot for interferon-{gamma HGNC}( IFN-{gamma}) HGNC and interleukin-4 HGNC ( IL-4 HGNC) secretion by T cells. On Study Day 56, all NHP were challenged with intratracheal/intranasal 1 x 106 TCID50/mL SARS-CoV-2. Bronchoalveolar lavage (BAL) samples were collected on Day 42 pre-challenge and at several time points post-challenge; nasal swabs were collected daily post-challenge. NHP were euthanized on Study Day 70 and tissue collected for histopathological analyses. Viral load and active viral replication were determined in BAL and nasal swab specimens by RT qPCR of genomic and subgenomic RNA, respectively. Safety was determined by cage-side observations such as weight as well as hematology and clinical chemistry analyses of blood. ResultsThe hAd5 S-Fusion + N-ETSD vaccine, both SC and oral, elicited no apparent toxicity MESHD seen in clinical chemistry, hematology, or cage-side observations. Neutralizing antibodies were induced in 9 of 10 vaccinated NHP and anti-S IgG positive titers in 10 out of 10. Th1 HGNC dominant T-cell responses were elicited by both S and N antigens, with responses being greater for N. Viral replication was inhibited from Day 1 post-SARS-CoV-2 challenge with complete protection in all (10/10) primates within 7 days of challenge from both nasal passages and lung. Replicating SARS-CoV-2 dropped immediately and was undetectable as soon 3 days post-challenge. There was a rapid decline in lymphocytes from the periphery on Day 1 post-challenge and a rebound within 3 days following challenge that was significantly higher by Day 14 post-challenge in Group 1 as compared to Group 3 placebo NHP. ConclusionsIn the rhesus macaque NHP model, the bivalent hAd5 S-Fusion + N-ETSD subcutaneous and oral vaccine provided complete protection of nasal passages and lung against SARS-CoV-2 challenge by eliciting neutralizing antibodies plus Th1 HGNC dominant N- and S-specific T-cell responses. Inhibition of viral replication within the first 24 hours post-challenge, in vaccinated NHP compared to placebo NHP, suggests the presence of SARS-CoV-2-specific cytotoxic T cells that rapidly cleared infected cells. The rapidity of clearance implies that shedding of live viruses may be attenuated as a result of vaccination and thus the vaccine has the potential to prevent transmission of virus by infected individuals. Clinical trials of hAd5 S-Fusion + N-ETSD are ongoing. The hAd5 S-Fusion + N-ETSD subcutaneous prime/boost vaccine has completed Phase 1 clinical trials and Phase 2/3 trials are actively recruiting. The thermally-stable oral vaccine will enter Phase 1 trials as a prime and boost, as well as explored to provide a boost to subcutaneous vaccination.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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