Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses.
TL;DR: In this article, the authors summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses.
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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TL;DR: In this paper, the authors used cryo-EM to capture structures of Nsp15 bound to RNA in pre-and post-cleavage states, and 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.
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.
36 citations
TL;DR: In this article, the angiotensin-converting enzyme 2 (ACE2) is used to treat COVID-19, which can convert a wide range of target molecules to restore the correct physiological metabolism.
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.
28 citations
TL;DR: Preliminary reasoning and judgments have been made about the possible mechanism of the effect of tea polyphenols on the COVID-19 control and prevention mediated by the microbiota and may be of great significance to the future exploration of specialized research in this field.
Abstract: Although all countries have taken corresponding measures, the coronavirus disease 2019 (COVID-19) is still ravaging the world. To consolidate the existing anti-epidemic results and further strengthen the prevention and control measures against the new coronavirus, we are now actively pioneering a novel research idea of regulating the intestinal microbiota through tea polyphenols for reference. Although studies have long revealed the regulatory effect of tea polyphenols on the intestinal microbiota to various gastrointestinal inflammations, little is known about the prevention and intervention of COVID-19. This review summarizes the possible mechanism of the influence of tea polyphenols on COVID-19 mediated by the intestinal microbiota. In this review, the latest studies of tea polyphenols exhibiting their own antibacterial and anti-inflammatory activities and protective effects on the intestinal mucosal barrier are combed through and summarized. Among them, (−)-epigallocatechin-3-gallate (EGCG), one of the main monomers of catechins, may be activated as nuclear factor erythroid 2 p45-related factor 2 (Nrf2). The agent inhibits the expression of ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2 to inhibit SARS-CoV-2 infection, inhibiting the life cycle of SARS-CoV-2. Thus, preliminary reasoning and judgments have been made about the possible mechanism of the effect of tea polyphenols on the COVID-19 control and prevention mediated by the microbiota. These results may be of great significance to the future exploration of specialized research in this field.
9 citations
TL;DR: In this article , the authors showed that RSV induced RNase2 expression, which significantly enhanced cell survival, and provided evidence of its cleavage selectivity on ncRNAs, which was confirmed in vitro using the recombinant protein.
Abstract: RNase2 is the member of the RNaseA family most abundant in macrophages. Here, we knocked out RNase2 in THP-1 cells and analysed the response to Respiratory Syncytial Virus (RSV). RSV induced RNase2 expression, which significantly enhanced cell survival. Next, by cP-RNAseq sequencing, which amplifies the cyclic-phosphate endonuclease products, we analysed the ncRNA population. Among the ncRNAs accumulated in WT vs KO cells, we found mostly tRNA-derived fragments (tRFs) and second miRNAs. Differential sequence coverage identified tRFs from only few parental tRNAs, revealing a predominant cleavage at anticodon and D-loops at U/C (B1) and A (B2) sites. Selective tRNA cleavage was confirmed in vitro using the recombinant protein. Likewise, only few miRNAs were significantly more abundant in WT vs RNase2-KO cells. Complementarily, by screening of a tRF & tiRNA array, we identified an enriched population associated to RNase2 expression and RSV exposure. The results confirm the protein antiviral action and provide the first evidence of its cleavage selectivity on ncRNAs.
6 citations
TL;DR: In this paper , the effects of CBD on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD).
Abstract: To study effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD). HEK293 cells transfected with plasmids expressing control vector, ORF8, ORF10, or M protein were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without CBD. Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection. Reduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1–2 μM CBD treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2′-5′-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. CBD similarly enhanced the cellular anti-viral response to Poly (I:C). Our results demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of CBD. Thus, CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.
6 citations
References
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TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
10,685 citations
TL;DR: This year’s update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years and 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.
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.
4,797 citations
TL;DR: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care, and future trials in patients withsevere illness may help to confirm or exclude the possibility of a treatment benefit.
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...
4,293 citations
TL;DR: This study determines the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2 and sheds light on the structural features that increase its binding affinity to ACE2.
Abstract: A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-191,2. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor—angiotensin-converting enzyme 2 (ACE2)—in humans3,4. Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD–ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2. The crystal structure of the receptor-binding domain of the SARS-CoV-2 spike in complex with human ACE2, compared with the receptor-binding domain of SARS-CoV, sheds light on the structural features that increase its binding affinity to ACE2.
3,019 citations
TL;DR: A brief introduction to coronaviruses is provided discussing their replication and pathogenicity, and current prevention and treatment strategies, and the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratories Syndrome Cor onavirus
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).
2,846 citations