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1.
Front Immunol ; 13:1080786, 2022.
Article in English | PubMed | ID: covidwho-2198918

ABSTRACT

Heat shock proteins (Hsps), including Hsp90 and Hsp70, are intra- and extracellular molecules implicated in cellular homeostasis and immune processes and are induced by cell stress such as inflammation and infection. Autoimmune bullous disorders (AIBDs) and COVID-19 represent potentially life-threatening inflammatory and infectious diseases, respectively. A significant portion of AIBDs remain refractory to currently available immunosuppressive therapies, which may represent a risk factor for COVID-19, and suffer from treatment side-effects. Despite advances in vaccination, there is still a need to develop new therapeutic approaches targeting SARS-CoV-2, especially considering vaccine hesitancy, logistical distribution challenges, and breakthrough infections. In this mini review, we briefly summarize the role of targeting Hsp90/70 as a promising double-edged sword in the therapy of AIBDs and COVID-19.

2.
Frontiers in Immunology ; 13:1033672, 2022.
Article in English | MEDLINE | ID: covidwho-2198879

ABSTRACT

B cell lymphoma 2 (BCL-2) family proteins are involved in the mitochondrial apoptotic pathway and are key modulators of cellular lifespan, which is dysregulated during human immunodeficiency virus type 1 (HIV-1) and other viral infections, thereby increasing the lifespan of cells harboring virus, including the latent HIV-1 reservoir. Long-lived cells harboring integrated HIV-1 DNA is a major barrier to eradication. Strategies reducing the lifespan of reservoir cells could significantly impact the field of cure research, while also providing insight into immunomodulatory strategies that can crosstalk to other viral infections. Venetoclax is a first-in-class orally bioavailable BCL-2 homology 3 (BH3) mimetic that recently received Food and Drug Administration (FDA) approval for treatment in myeloid and lymphocytic leukemia. Venetoclax has been recently investigated in HIV-1 and demonstrated anti-HIV-1 effects including a reduction in reservoir size. Another immunomodulatory strategy towards reduction in the lifespan of the reservoir is Jak 1/2 inhibition. The Jak STAT pathway has been implicated in BCL-2 and interleukin 10 (IL-10) expression, leading to a downstream effect of cellular senescence. Ruxolitinib and baricitinib are FDA-approved, orally bioavailable Jak 1/2 inhibitors that have been shown to indirectly decay the HIV-1 latent reservoir, and down-regulate markers of HIV-1 persistence, immune dysregulation and reservoir lifespan in vitro and ex vivo. Ruxolitinib recently demonstrated a significant decrease in BCL-2 expression in a human study of virally suppressed people living with HIV (PWH), and baricitinib recently received emergency use approval for the indication of coronavirus disease 2019 (COVID-19), underscoring their safety and efficacy in the viral infection setting. BCL-2 and Jak 1/2 inhibitors could be repurposed as immunomodulators for not only HIV-1 and COVID-19, but other viruses that upregulate BCL-2 anti-apoptotic proteins. This review examines potential routes for BCL-2 and Jak 1/2 inhibitors as immunomodulators for treatment and cure of HIV-1 and other viral infections.

3.
7th International Conference on Advanced Production and Industrial Engineering, ICAPIE 2022 ; 27:565-570, 2022.
Article in English | Scopus | ID: covidwho-2198468

ABSTRACT

The pandemic that started in 2019 in Wuhan caused a vast number of deaths worldwide due to the absence of effective therapy against SARS-CoV-2. The present study investigates the interaction of AMP with viral protein and host receptors. We screened plant-derived antimicrobial peptides (AMP) from the docking web server with the help of PDB ID. We selected five anti-microbial peptides based on their antiviral and physiological activities. The interaction of anti-microbial peptide and Mpro was analyzed using the HADDOCK web server. The results revealed that the minimum Z-score was obtained by the 6LU7-1N4N complex followed by 6LU7-1GPS docked complex. The docking results showed the interaction potency of AMP with 6LU7. The dynamic simulation study of 100ns was performed to check the stability of the docked complexes of AMP and 6LU7. From the stable and positive results of dynamics studies, we can conclude that these selected AMPs have immense potential to be used as therapeutic agents for the treatment of disease. © 2022 The authors and IOS Press.

4.
IPSJ Transactions on Bioinformatics ; 15:22-29, 2022.
Article in English | Scopus | ID: covidwho-2198188

ABSTRACT

A method to find a probability that a given bias of mutations occur naturally is proposed to test whether a newly detected virus is a product of natural evolution or a product of non-natural process such as genetic manipulation. The probability is calculated based on the neutral theory of molecular evolution and binominal distribution of non-synonymous (N) and synonymous (S) mutations. Though most of the conventional analyses, including dN/dS analysis, assume that any kinds of point mutations from a nucleotide to another nucleotide occurs with the same probability, the proposed model takes into account the bias in mutations, where the equilibrium of mutations is considered to estimate the probability of each mutation. The proposed method is applied to evaluate whether the Omicron variant strain of SARS-CoV-2, whose spike protein includes 29 N mutations and only one S mutation, can emerge through natural evolution. The result of binomial test based on the proposed model shows that the bias of N/S mutations in the Omicron spike can occur with a probability of 2.0 × 10−3 or less. Even with the conventional model where the probabilities of any kinds of mutations are all equal, the strong N/S mutation bias in the Omicron spike can occur with a probability of 3.7 × 10−3, which means that the Omicron variant is highly likely a product of non-natural process including artifact. © 2022 Information Processing Society of Japan.

5.
PLoS Pathogens ; 18(12):e1011041, 2022.
Article in English | MEDLINE | ID: covidwho-2197181

ABSTRACT

Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the pandemic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation and SG formation induced by exogenous stress. Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2alpha phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause a decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear accumulation of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in virus replication compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

6.
Genome Biology ; 23:1-19, 2022.
Article in English | ProQuest Central | ID: covidwho-2196402

ABSTRACT

Spatial omics technologies enable a deeper understanding of cellular organizations and interactions within a tissue of interest. These assays can identify specific compartments or regions in a tissue with differential transcript or protein abundance, delineate their interactions, and complement other methods in defining cellular phenotypes. A variety of spatial methodologies are being developed and commercialized;however, these techniques differ in spatial resolution, multiplexing capability, scale/throughput, and coverage. Here, we review the current and prospective landscape of single cell to subcellular resolution spatial omics technologies and analysis tools to provide a comprehensive picture for both research and clinical applications.

7.
2022 International Conference on Biomedical and Intelligent Systems, IC-BIS 2022 ; 12458, 2022.
Article in English | Scopus | ID: covidwho-2193342

ABSTRACT

The new virus was initially defined in Wuhan, China, in 2019. Because of its quick transmission, a pandemic spread over the world. The SARS-CoV-2 virus is a subtype of the coronavirus family, the seventh virus type after SARS. The virus enters organisms' cells and produces mRNA in the host cell through a series of processes including replication and transcription. mRNA is translated into the corresponding viral protein in the cell and released from the host cell. To stop the spread of the disease, various vaccines have been developed and put into use in a short time. This paper details the design of a newer type of mRNA vaccine against COVID-19, its advantages and disadvantages, and compares it with other types of vaccines. The comparison reveals that mRNA vaccines have apparent advantages in terms of speed of production and safety, but at the same time their delivery conditions and instability are issues that need to be addressed. If the mRNA vaccines' storage conditions are improved, such as by raising the temperature at which they are stored, extending their half-life, and lowering the stringent storage standards, in the future, mRNA vaccines will play a larger clinical role. © 2022 SPIE. All rights reserved.

8.
Immunology & Cell Biology ; 101(1):6-8, 2023.
Article in English | Academic Search Complete | ID: covidwho-2192652

ABSTRACT

Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19. [1] Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19. Given the recently appreciated role of B cells in MS, Marsh-Wakefield I et al i .[8] used mass cytometry and single-cell RNA sequencing to create a clear picture of B-cell dysregulation concordant with MS relapse. [Extracted from the article]

9.
2022 International Conference on Recent Advances in Electrical Engineering and Computer Sciences, RAEE and CS 2022 ; 2022.
Article in English | Scopus | ID: covidwho-2192050

ABSTRACT

Drug repurposing is the technique of finding new uses for currently used or under-researched drugs. Because this strategy requires less time and money, it is thought to be a particularly effective drug development strategy. Due to current technological breakthroughs, the accessibility of vast and reliable database resources, as well as data accessibility from genomes, proteomics, transcriptomics, etc., there are numerous opportunities to identify drugs by drug repurposing. The recent SARS-COV-2 epidemic, which has so far claimed 6,245,750 lives, has significantly increased the use of bioinformatics techniques in deciphering the characteristics of viral diseases. Using FDA-approved antiviral drugs that target the COVID-19 spike protein, we have used a bioinformatics approach to drug repurposing to find possible effective inhibitors against the Coronavirus (COVID-19). We used a variety of bioinformatics tools in this study, including AutoDock-Vina, PyMol, and Discovery Studio, to identify a promising drug called Cepharanthine (CEP), which demonstrates successful outcomes and efficacy compared to recently used antiviral drug candidates like arbidol, talampicillin, bromhexine, chloroquine, lycorine, bruceine A, reserpine, indinavir, galidesiver, doxycycline, methisazone, flupentixol, trifluoperazine and fluoxetine. The potential therapeutic value of cepharanthine as a drug for treating COVID-19 has been investigated in this study. It is expected that the proposed study will help medical professionals and researchers cure disorders linked to Severe acute respiratory and variations of it. © 2022 IEEE.

10.
2022 International Conference on Information Technology Research and Innovation, ICITRI 2022 ; : 1-5, 2022.
Article in English | Scopus | ID: covidwho-2191887

ABSTRACT

Drugs are generally designed for a specific target protein. Recent studies have demonstrated the capability of deep learning-based models to accelerate and cheapen the drug development process. The proposed deep learning models can generate novel molecules with optimized drug-like properties. However, the properties addressed are often limited and may be misleading. This is because they do not reflect the complete information about the binding affinity of the designed drug and the target protein. In this work, we exploit the state-of-The-Art progress made in drug-Target-Affinity (DTA) prediction to assess the binding affinity of drugs generated by a developed molecular generator against the corona-virus main protease (SARS-CoV-2 Mpro). The molecular generator is a recurrent neural network-based model, while the DTA predictor is a graph neural network (GNN), famously known as GraphDTA. We train the molecular generator using reinforcement learning (RL) to optimize the GraphDTA-predicted score. As this is the first benchmark of this kind (to the best of our knowledge), we report our benchmarking results;of 1.79% desirability;with the hope of motivating future improvements in this regard. © 2022 IEEE.

11.
22nd IEEE International Conference on Bioinformatics and Bioengineering, BIBE 2022 ; : 146-151, 2022.
Article in English | Scopus | ID: covidwho-2191683

ABSTRACT

Commonly in pandemic times, curfew and social restrictions are applied in order to minimize the infections. As seen recently at the beginning of Covid-19 it was required that people avoid public spaces because the risk of infection due to transmission through aerosols. This paper proposes a theory of Internet of Pandemic Things Network that consists in four fundamental steps: (i) Bio-sensing of virus in open places, (ii) Sending to the network of report about the virus characteristics, (iii) Emission of innocuous radiation within a limited spatial coverage and (iv) checking out of radiated area if apt for public usage. In this manner equations from classical electrodynamics are derived in closed-form. Essentially it is presented a theory that aims to neutralize electrically charged proteins of virus in open places. Simulations based at this are presented. © 2022 IEEE.

12.
Nucleic Acids Research ; 51(1):475-487, 2023.
Article in English | MEDLINE | ID: covidwho-2189415

ABSTRACT

NSP14 is a dual function enzyme containing an N-terminal exonuclease domain (ExoN) and C-terminal Guanine-N7-methyltransferase (N7-MTase) domain. Both activities are essential for the viral life cycle and may be targeted for anti-viral therapeutics. NSP14 forms a complex with NSP10, and this interaction enhances the nuclease but not the methyltransferase activity. We have determined the structure of SARS-CoV-2 NSP14 in the absence of NSP10 to 1.7 A resolution. Comparisons with NSP14/NSP10 complexes reveal significant conformational changes that occur within the NSP14 ExoN domain upon binding of NSP10, including helix to coil transitions that facilitate the formation of the ExoN active site and provide an explanation of the stimulation of nuclease activity by NSP10. We have determined the structure of NSP14 in complex with cap analogue 7MeGpppG, and observe conformational changes within a SAM/SAH interacting loop that plays a key role in viral mRNA capping offering new insights into MTase activity. We perform an X-ray fragment screen on NSP14, revealing 72 hits bound to sites of inhibition in the ExoN and MTase domains. These fragments serve as excellent starting point tools for structure guided development of NSP14 inhibitors that may be used to treat COVID-19 and potentially other future viral threats.

13.
Nucleic Acids Research ; 51(1):290-303, 2023.
Article in English | MEDLINE | ID: covidwho-2189413

ABSTRACT

The SARS-CoV-2 nucleocapsid (N) protein performs several functions including binding, compacting, and packaging the ~30 kb viral genome into the viral particle. N protein consists of two ordered domains, with the N terminal domain (NTD) primarily associated with RNA binding and the C terminal domain (CTD) primarily associated with dimerization/oligomerization, and three intrinsically disordered regions, an N-arm, a C-tail, and a linker that connects the NTD and CTD. We utilize an optical tweezers system to isolate a long single-stranded nucleic acid substrate to measure directly the binding and packaging function of N protein at a single molecule level in real time. We find that N protein binds the nucleic acid substrate with high affinity before oligomerizing and forming a highly compact structure. By comparing the activities of truncated protein variants missing the NTD, CTD, and/or linker, we attribute specific steps in this process to the structural domains of N protein, with the NTD driving initial binding to the substrate and ensuring high localized protein density that triggers interprotein interactions mediated by the CTD, which forms a compact and stable protein-nucleic acid complex suitable for packaging into the virion.

14.
Nucleic Acids Research ; 51(1):315-336, 2023.
Article in English | MEDLINE | ID: covidwho-2189412

ABSTRACT

Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3'-to-5' proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3'-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3'-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.

15.
Metallomics : integrated biometal science ; 04, 2023.
Article in English | EMBASE | ID: covidwho-2189399

ABSTRACT

Metalloproteins are well-known for playing various physicochemical processes in all life forms, including viruses. Some life-threatening viruses (such as some members of the coronaviridae family of viruses) are emerged and remerged frequently and are rapidly transmitted throughout the globe. This study aims to identify and characterize the metal-binding proteins of the coronaviridae family of viruses and further provides insight into the metal-binding protein's role in sustaining and propagating viruses inside a host cell and in the outer environment. In the present study, the available proteome of the coronaviridae family was exploited. Identified potential metal-binding proteins were analyzed for their functional domains, structural aspects, and sub-cellular localization. We also demonstrate phylogenetic aspects of all predicted metal-binding proteins among other coronaviridae family members to understand the evolutionary trend among their respective hosts. A total of 256 proteins from 51 different species of coronaviruses are predicted as metal-binding proteins. These metal-binding proteins perform various key roles in the replication and survival of viruses within the host cell. Cysteine, aspartic acid, threonine, and glutamine are key amino acid residues interacting with respective metal ions. Our observations also indicate that the metalloproteins of this family of viruses circulated and evolved in different hosts, which supports the zoonotic nature of coronaviruses. The comprehensive information on metal-binding proteins of the coronaviridae family may be further helpful in designing novel therapeutic metalloprotein targets. Moreover, the study of viral metal-binding proteins can also help to understand the roles of metal-binding proteins in virus pathogenesis and virus-host interactions. Copyright © The Author(s) 2023. Published by Oxford University Press.

16.
Human Gene Therapy ; 33(23-24):A1-A212, 2022.
Article in English | Academic Search Complete | ID: covidwho-2188077

ABSTRACT

P700 A novel platform for engineered AAV-based vaccines S Babutzka SP 1 sp L Zobel SP 1 sp J Bogedein SP 1 sp M Diedrichs-Möhring SP 1 sp M Gehrke SP 1 sp G Wildner SP 1 sp H Ammer SP 2 sp S Michalakis SP 1 sp I 1: Department of Ophthalmology, University Hospital, LMU Munich, 80336 Munich, Germany 2: Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, Munich, Germany i The still ongoing pandemic has highlighted the unmet need for more innovative and rapidly adaptable vaccine platforms. P702 Circumventing anti-vector immunity towards adenoviral vectored vaccines C M Bliss SP 1 sp J A Davies SP 1 sp M Marusková SP 1 sp L M Badder SP 1 sp M A Oliver SP 2 sp L Stack SP 1 sp A T Baker SP 1 sp A L Parker SP 1 sp I 1: Cardiff University 2: InBio i Replication deficient (RD) adenoviruses (Ad) are the most widely administered viral vectors, with licensed SARS-CoV-2 vaccines using vectors derived from human Ad type 5 (Ad5) and 26 (Ad26), and chimpanzee Ad " I ChAdOx1 i ". P704 Characterization of adenovirus interactions with PF4 using a novel ELISA-qPCR technology E Sallard SP 1 sp F Kreppel SP 1 sp A Ehrhardt SP 1 sp I 1: Witten/Herdecke University i The COVID vaccines Janssen and AstraZeneca, based respectively on adenovirus (AdV) serotypes AdV26 and ChAdOx1, have been associated with rare cases of vaccine-induced thrombotic thrombocytopenia (VITT). This next-generation vaccine platform based on AAV capsids with large insertions of immunogenic sequences enables strong and specific immune responses without the need for genomically encoded immunogens, thus reducing the risk of potentially pathogenic intracellular processes associated with viral vector genomes and prolonged transgene expression. [Extracted from the article]

17.
NPJ Vaccines ; 7(1):166, 2022.
Article in English | ProQuest Central | ID: covidwho-2185872

ABSTRACT

Experimental vaccines for the deadly zoonotic Nipah (NiV), Hendra (HeV), and Ebola (EBOV) viruses have focused on targeting individual viruses, although their geographical and bat reservoir host overlaps warrant creation of multivalent vaccines. Here we explored whether replication-incompetent pseudotyped vesicular stomatitis virus (VSV) virions or NiV-based virus-like particles (VLPs) were suitable multivalent vaccine platforms by co-incorporating multiple surface glycoproteins from NiV, HeV, and EBOV onto these virions. We then enhanced the vaccines' thermotolerance using carbohydrates to enhance applicability in global regions that lack cold-chain infrastructure. Excitingly, in a Syrian hamster model of disease, the VSV multivalent vaccine elicited safe, strong, and protective neutralizing antibody responses against challenge with NiV, HeV, or EBOV. Our study provides proof-of-principle evidence that replication-incompetent multivalent viral particle vaccines are sufficient to provide protection against multiple zoonotic deadly viruses with high pandemic potential.

18.
Nature ; 613(7943):222-223, 2023.
Article in English | ProQuest Central | ID: covidwho-2185709

ABSTRACT

The XBB.1.5 subvariant now makes up around 28% of US COVID-19 cases, according to projections from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and its prevalence is on the rise globally. Tulio de Oliveira, a bioinformatician at Stellenbosch University in South Africa, thinks researchers should look at hospital cases and other measures of disease severity to best measure XBB.1.5's impact. Factors such as a cold snap in the northeastern United States and holiday gatherings could partly explain the variant's apparent surge, he says.

19.
Nature ; 613(7942):13-14, 2023.
Article in English | ProQuest Central | ID: covidwho-2185695

ABSTRACT

During the year of a contest, teams are tasked with using computational tools to predict the structures of proteins that have been determined using experimental methods such as X-ray crystallography and cryo-electron microscopy, but not yet released. Some of AlphaFold's predictions at CASP14 were more or less indistinguishable from the experimental models - the first time such accuracy had been achieved. Since its unveiling at CASP14, AlphaFold has become omnipresent in life-sciences research. The standard version of AlphaFold failed to accurately model the shape of a giant, 20-chain bacterial enzyme, but some teams predicted the protein's structure by applying extra hacks to the network, Karaca adds.

20.
Nature ; 612(7941):614, 2022.
Article in English | ProQuest Central | ID: covidwho-2185685

ABSTRACT

Confronted with the prospect of stopping work, Cao realized that the methods he had specialized in could be used to study the antibodies triggered by infection with SARS-CoV-2. Cao - who leads much of the COVID-19 work in Xie's group - started his pandemic efforts by screening people who had recovered from COVID-19 for antibodies that could be used in treatment. Working with a Chinese drug company, the group picked two of the most potent infection-blocking, or neutralizing, antibodies and began trialling them in people with COVID-19.

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