Remdesivir targets a structurally analogous region of the Ebola virus and SARS-CoV-2 polymerases.
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ABSTRACT:
SUBMITTER: Lo MK
PROVIDER: S-EPMC7604432 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We have previously shown that the first transcription start signal (TSS) of Zaire Ebola virus (ZEBOV) is involved in formation of an RNA secondary structure regulating VP30-dependent transcription activation. Interestingly, transcription of Marburg virus (MARV) minigenomes occurs independently of VP30. In this study, we analyzed the structure of the MARV 3' noncoding region and its influence on VP30 necessity. Secondary structure formation of the TSS of the first gene was experimentally determined and showed substantial differences from the structure formed by the ZEBOV TSS. Chimeric MARV minigenomes mimicking the ZEBOV-specific RNA secondary structure were neither transcribed nor replicated. Mapping of the MARV genomic replication promoter revealed that the region homologous to the sequence involved in formation of the regulatory ZEBOV RNA structure is part of the MARV promoter. The MARV promoter is contained within the first 70 nucleotides of the genome and consists of two elements separated by a spacer region, comprising the TSS of the first gene. Mutations within the spacer abolished transcription activity and led to increased replication, indicating competitive transcription and replication initiation. The second promoter element is located within the nontranslated region of the first gene and consists of a stretch of three UN(5) hexamers. Recombinant full-length MARV clones, in which the three conserved U residues were substituted, could not be rescued, underlining the importance of the UN(5) hexamers for replication activity. Our data suggest that differences in the structure of the genomic replication promoters might account for the different transcription strategies of Marburg and Ebola viruses.
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Project description:SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a microRNA (miRNA) derived from a recently evolved region of the viral genome. We show that the virus-derived miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3´UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 can potentially employ a virus-derived miRNA to hijack the host miRNA machinery which can lead to evasion of the interferon-mediated immune response.
| S-SCDT-EMBOR-2021-54341-T | biostudies-other
Project description:Remdesivir is an antiviral drug initially designed against the Ebola virus. The results obtained with it both in biochemical studies in vitro and in cell line assays in vivo were very promising, but it proved to be ineffective in clinical trials. Remdesivir exhibited far better efficacy when repurposed against SARS-CoV-2. The chemistry that accounts for this difference is the subject of this study. Here, we examine the hypothesis that remdesivir monophosphate (RMP)-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis. Our hypothesis is supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases (RdRps) of both viruses, although some of the incorporated RMPs are subsequently removed by exoribonucleases. Furthermore, our hypothesis is consistent with the fact that RdRp of SARS-CoV-2 selects RMP for incorporation over AMP by 3-fold in vitro, and that RMP-added RNA can be rapidly extended, even though primer extension is often paused when the added RMP is translocated at the i + 3 position (with i the nascent base pair at an initial insertion site of RMP) or when the concentrations of the subsequent nucleoside triphosphates (NTPs) are below their physiological concentrations. These observations have led to the hypothesis that remdesivir might be a delayed chain terminator. However, that hypothesis is challenged under physiological concentrations of NTPs by the observation that approximately three-quarters of RNA products efficiently overrun the pause.
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Project description:Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5'-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.
| S-EPMC7589801 | biostudies-literature
Project description:Ebola virus is among the most dangerous, contagious and deadly etiological causes of viral diseases. However, Ebola virus has never extensively spread in human population and never have led to a pandemic. Why? The mechanistic biophysical model revealing the biothermodynamic background of virus-host interaction) could help us to understand pathogenesis of Ebola virus disease (earlier known as the Ebola hemorrhagic fever). In this paper for the first time the empirical formula, thermodynamic properties of biosynthesis (including the driving force of virus multiplication in the susceptible host), binding constant and thermodynamic properties of binding are reported. Thermodynamic data for Ebola virus were compared with data for SARS-CoV-2 to explain why SARS-CoV-2 has caused a pandemic, while Ebola remains on local epidemic level. The empirical formula of the Ebola virus was found to be CH1.569O0.3281N0.2786P0.00173S0.00258. Standard Gibbs energy of biosynthesis of the Ebola virus nucleocapsid is -151.59 kJ/C-mol.
| S-EPMC9597532 | biostudies-literature
Project description:Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.
| S-EPMC8484580 | biostudies-literature
Project description:Remdesivir (GS-5734) is a 1'-cyano-substituted adenosine nucleotide analogue prodrug that shows broad-spectrum antiviral activity against several RNA viruses. This compound is currently under clinical development for the treatment of Ebola virus disease (EVD). While antiviral effects have been demonstrated in cell culture and in non-human primates, the mechanism of action of Ebola virus (EBOV) inhibition for remdesivir remains to be fully elucidated. The EBOV RNA-dependent RNA polymerase (RdRp) complex was recently expressed and purified, enabling biochemical studies with the relevant triphosphate (TP) form of remdesivir and its presumptive target. In this study, we confirmed that remdesivir-TP is able to compete for incorporation with adenosine triphosphate (ATP). Enzyme kinetics revealed that EBOV RdRp and respiratory syncytial virus (RSV) RdRp incorporate ATP and remdesivir-TP with similar efficiencies. The selectivity of ATP against remdesivir-TP is ~4 for EBOV RdRp and ~3 for RSV RdRp. In contrast, purified human mitochondrial RNA polymerase (h-mtRNAP) effectively discriminates against remdesivir-TP with a selectivity value of ~500-fold. For EBOV RdRp, the incorporated inhibitor at position i does not affect the ensuing nucleotide incorporation event at position i+1. For RSV RdRp, we measured a ~6-fold inhibition at position i+1 although RNA synthesis was not terminated. Chain termination was in both cases delayed and was seen predominantly at position i+5. This pattern is specific to remdesivir-TP and its 1'-cyano modification. Compounds with modifications at the 2'-position show different patterns of inhibition. While 2'-C-methyl-ATP is not incorporated, ara-ATP acts as a non-obligate chain terminator and prevents nucleotide incorporation at position i+1. Taken together, our biochemical data indicate that the major contribution to EBOV RNA synthesis inhibition by remdesivir can be ascribed to delayed chain termination. The long distance of five residues between the incorporated nucleotide analogue and its inhibitory effect warrant further investigation.
| S-EPMC6520719 | biostudies-literature
Project description:Viruses rely on the cellular machinery to replicate and propagate within newly infected individuals. Thus, viral entry into the host cell sets up the stage for productive infection and disease progression. Different viruses exploit distinct cellular receptors for viral entry; however, numerous viral internalization mechanisms are shared by very diverse viral families. Such is the case of Ebola virus (EBOV), which belongs to the filoviridae family, and the recently emerged coronavirus SARS-CoV-2. These two highly pathogenic viruses can exploit very similar endocytic routes to productively infect target cells. This convergence has sped up the experimental assessment of clinical therapies against SARS-CoV-2 previously found to be effective for EBOV, and facilitated their expedited clinical testing. Here we review how the viral entry processes and subsequent replication and egress strategies of EBOV and SARS-CoV-2 can overlap, and how our previous knowledge on antivirals, antibodies, and vaccines against EBOV has boosted the search for effective countermeasures against the new coronavirus. As preparedness is key to contain forthcoming pandemics, lessons learned over the years by combating life-threatening viruses should help us to quickly deploy effective tools against novel emerging viruses.
| S-EPMC7830673 | biostudies-literature
Project description:Correlates of protection (CoP) are biological parameters that predict a certain level of protection against an infectious disease. Well-established correlates of protection facilitate the development and licensing of vaccines by assessing protective efficacy without the need to expose clinical trial participants to the infectious agent against which the vaccine aims to protect. Despite the fact that viruses have many features in common, correlates of protection can vary considerably amongst the same virus family and even amongst a same virus depending on the infection phase that is under consideration. Moreover, the complex interplay between the various immune cell populations that interact during infection and the high degree of genetic variation of certain pathogens, renders the identification of immune correlates of protection difficult. Some emerging and re-emerging viruses of high consequence for public health such as SARS-CoV-2, Nipah virus (NiV) and Ebola virus (EBOV) are especially challenging with regards to the identification of CoP since these pathogens have been shown to dysregulate the immune response during infection. Whereas, virus neutralising antibodies and polyfunctional T-cell responses have been shown to correlate with certain levels of protection against SARS-CoV-2, EBOV and NiV, other effector mechanisms of immunity play important roles in shaping the immune response against these pathogens, which in turn might serve as alternative correlates of protection. This review describes the different components of the adaptive and innate immune system that are activated during SARS-CoV-2, EBOV and NiV infections and that may contribute to protection and virus clearance. Overall, we highlight the immune signatures that are associated with protection against these pathogens in humans and could be used as CoP.
| S-EPMC10158532 | biostudies-literature
Project description:RNA sequencing was performed on control and SARS-CoV-2 infected Vero E6 cells, with or without remdesivir treatment to study the biological changes after SARS-CoV-2 infection and to evaluate the effectiveness of remdesivir on the gene expression level. 500,000 Vero E6 cells were seeded in 6-well plates. The following day, the cell medium was replaced with fresh medium supplemented with either DMSO or 1 µM remdesivir, and cells were either mock-infected or infected with SARS-CoV-2 USA-WA1/2020 (MOI=0.3), with three replicates per experimental condition. Cells were harvested 24 hours after infection, and total RNA was extracted using the Qiagen® RNeasy® Plus Mini Kit. The quality of the extracted RNA was assessed with the Agilent® 2100 Bioanalyzer. Libraries were prepared from total RNA following ribosome RNA depletion using standard protocol according to Illumina®. Total RNA sequencing was then performed on the Illumina® NextSeq system; 150bp paired-end runs were performed and 100 million raw reads per sample were generated.
2021-02-02 | GSE165955 | GEO