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Open accessJournal ArticleDOI: 10.1080/21505594.2021.1871823

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses.

04 Mar 2021-Virulence (Taylor & Francis)-Vol. 12, Iss: 1, pp 444-469
Abstract: Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time. Here, we try to summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses. Overall, host RNases can fight viruses by a combined multifaceted strategy, including the enzymatic target of the viral genome, recognition of virus unique patterns, immune modulation, control of stress granule formation, and induction of autophagy/apoptosis pathways. The review also includes a detailed description of representative enveloped ssRNA viruses and their strategies to interact with the host and evade immune recognition. For comparative purposes, we also provide an exhaustive revision of the currently approved or experimental antiviral drugs. Finally, we sum up the current perspectives of drug development to achieve successful eradication of viral infections.

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Topics: Coronavirus (50%)
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7 results found


Open accessPosted ContentDOI: 10.1101/2021.06.01.446181
01 Jun 2021-bioRxiv
Abstract: Nsp15 is a uridine specific endoribonuclease that coronaviruses employ to cleave viral RNA and evade host immune defense systems. Previous structures of Nsp15 from across Coronaviridae revealed that Nsp15 assembles into a homo-hexamer and has a conserved active site similar to RNase A. Beyond a preference for cleaving RNA 3 of uridines, it is unknown if Nsp15 has any additional substrate preferences. Here we used cryo-EM to capture structures of Nsp15 bound to RNA in pre- and post-cleavage states. The structures along with molecular dynamics and biochemical assays revealed critical residues involved in substrate specificity, nuclease activity, and oligomerization. Moreover, we determined how the sequence of the RNA substrate dictates cleavage and found that outside of polyU tracts, Nsp15 has a strong preference for purines 3 of the cleaved uridine. This work advances our understanding of how Nsp15 recognizes and processes viral RNA and will aid in the development of new anti-viral therapeutics.

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Topics: RNA (60%), Endoribonuclease (59%), RNase P (57%) ... read more

1 Citations


Open accessJournal Article
Abstract: This study attempted to evaluate the scholarly publications on COVID-19, social distance, physical distance, social isolation, and self-isolation employing the scientometric analysis technique from 2020 to 2021. The main purpose was to consolidate the published scholarship on the COVID-19 in the Web of Science indexed documents. A total of 635 publications were found. The results indicated that social distance and COVID-19 was the top topic along with the article as a type of document, and the majority were published in the English language in 2021. The name of Gimenez-Llort L was at top of the list of authors, along with Univ. British Columbia, Canada organization, United States top country, COVID-19 as to keyword of the published documents and the main source of publication was PLOS One. Further, we had constructed figures and tables to show the trend of data. © 2021. All Rights Reserved.

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Topics: Social distance (51%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/IJMS22179181
Abstract: In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.

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1 Citations


Open accessJournal ArticleDOI: 10.47059/REVISTAGEINTEC.V11I2.1779
04 Jun 2021-
Abstract: Aim: The main objective of this study is to compare and analyse human prostasomes amino acid content variation in normal men semen samples and infertile men semen samples for identification of clinical relevance. Materials and methods: Semen samples were collected from normal men (N=32) and from infertile men (N=32) and by following the standard world health organisation protocol semen analysis was done. Amino acid quantification was done by using amino acid analyzer. Prostasomes were separated from spermatozoa and seminal plasma by using centrifugation technique at 95000 RPM for 90 mins. Results: Independent sample T-test was carried out and shows that proline and alanine amino acids concentration (p<0.01) statistically significant compared with fertile men and infertile men. High concentration of amino acids in prostasomes were found in fertile men samples (18.09 ± 0.20 μmoles/L) when compared with infertile men samples (15.12± 0.37 μmoles/L). Conclusion: Amino acid in prostasomes plays an important role in the fertilization; the change in the concentration of amino acid in prostasomes leads to infertility of men. Here we found that the concentration of amino acids is high in fertile men when compared to infertile men which could act as an innovative diagnosis method for infertility.

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Topics: Prostasomes (59%), Male infertility (54%), Semen analysis (52%) ... read more

Open accessPosted ContentDOI: 10.1101/2021.08.30.458223
Lu Lu1, Jiarui Li, RanLei Wei2, Irene Guidi  +4 moreInstitutions (2)
31 Aug 2021-bioRxiv
Abstract: RNase2, also named the Eosinophil derived Neurotoxin (EDN), is one of the main proteins secreted by the eosinophil secondary granules. RNase2 is also expressed in other leukocyte cells and is the member of the human ribonuclease A family most abundant in macrophages. The protein is endowed with a high ribonucleolytic activity and participates in the host antiviral activity. Although RNase2 displays a broad antiviral activity, it is mostly associated to the targeting of single stranded RNA viruses. To explore RNase2 mechanism of action in antiviral host defence we knocked out RNase2 expression in the THP1 monocyte cell line and characterized the cell response to human Respiratory Syncytial Virus (RSV). We observed that RSV infection induced the RNase2 expression and protein secretion in THP1 macrophage-derived cells, whereas the knockout (KO) of RNase2 resulted in higher RSV burden and reduced cell viability. Next, by means of the cP-RNAseq methodology, which uniquely amplifies the RNA 2939cyclic-phosphate-end products released by an endonuclease cleavage, we compared the ncRNA population in native and RNase2-KO cell lines. Among the ncRNAs accumulated in WT versus KO cells, we found mostly tRNA-derived fragments and secondly miRNAs. Analysis of the differential sequence coverage of tRNAs molecules in native and KO cells identified fragments derived from only few parental tRNAs, revealing a predominant cleavage at anticodon loops and secondarily at D-loops. Inspection of cleavage region identified U/C and A, at 59 and 39 sides of cleavage sites respectively (namely RNase B1 and B2 base binding subsites). Likewise, only few selected miRNAs were significantly more abundant in WT versus RNase2-KO cells, with cleavage sites located at the end of stem regions with predominance for pyrimidines at B1 but following an overall less defined nucleotide specificity. Complementarily, by screening of a tRF/tiRNA PCR array we identified an enriched population of tRNA-derived fragments associated to RNase2 expression and RSV infection. The present results confirm the contribution of the protein in macrophage response against virus infection and provide the first evidence of its cleavage selectivity against ncRNA population. A better understanding of the mechanism of action of RNase2 recognition of cellular RNA during the antiviral host defence should pave the basis for the design of novel antiviral drugs.

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Topics: RNA (54%), RNase P (53%), Population (53%) ... read more

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339 results found


Open accessJournal ArticleDOI: 10.1016/J.CELL.2006.02.015
24 Feb 2006-Cell
Abstract: Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

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Topics: Pattern recognition receptor (67%), Innate immune system (65%), Acquired immune system (65%) ... read more

9,733 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2001282
Bin Cao1, Yeming Wang1, Danning Wen2, Wen Liu2  +61 moreInstitutions (7)
Abstract: Background No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. Methods We conducted a randomized, controlled, open-label trial involvin...

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Topics: Lopinavir/ritonavir (63%), Lopinavir (60%), Randomized controlled trial (53%) ... read more

3,577 Citations


Open accessJournal ArticleDOI: 10.1093/NAR/GKX1037
Abstract: DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education.

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Topics: DrugBank (81%)

2,626 Citations


Open accessBook ChapterDOI: 10.1007/978-1-4939-2438-7_1
Anthony R. Fehr1, Stanley Perlman1Institutions (1)
Abstract: Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. Coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease in chickens to potentially lethal human respiratory infections. Here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and current prevention and treatment strategies. We also discuss the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV).

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Topics: Coronavirus (68%), Viral replication (50%)

2,137 Citations


Open accessJournal ArticleDOI: 10.1016/S0140-6736(10)60206-1
Harish Nair1, Harish Nair2, D. James Nokes3, D. James Nokes4  +21 moreInstitutions (14)
01 May 2010-The Lancet
Abstract: Summary Background The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005. Methods We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality. Findings In 2005, an estimated 33·8 (95% CI 19·3–46·2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3·4 (2·8–4·3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000–199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting. Interpretation Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority. Funding WHO; Bill & Melinda Gates Foundation.

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Topics: Case fatality rate (52%), Population (51%)

2,052 Citations


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No. of citations received by the Paper in previous years
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20217