The Inhibition of RNA Viruses by Amaryllidaceae Alkaloids: Opportunities for the Development of Broad‐Spectrum Anti‐Coronavirus Drugs

2022 ◽  
Author(s):  
Shen Tan ◽  
Martin G. Banwell ◽  
Wen‐Cai Ye ◽  
Ping Lan ◽  
Lorenzo V. White
Keyword(s):  
Broad Spectrum ◽  
Rna Viruses ◽  
Amaryllidaceae Alkaloids

scholarly journals Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

2020 ◽  
Vol 28 ◽  
pp. 204020662097678
Author(s):  
Johanna Huchting
Keyword(s):  
Broad Spectrum ◽  
Viral Genome ◽  
De Novo ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Drug ◽  
Building Blocks ◽  
Structural Features ◽  
Pathogen Transmission ◽  
Nucleotide Synthesis

Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

scholarly journals Correction to: Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

2020 ◽  
Author(s):  
Rui Xiong ◽  
Leike Zhang ◽  
Shiliang Li ◽  
Yuan Sun ◽  
Minyi Ding ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Rna Viruses ◽  
Original Publication ◽  
Correct Figure

In the original publication there are few errors in Figure 1. The correct Figure 1 is provided in this correction

scholarly journals Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

2020 ◽  
Author(s):  
Rui Xiong ◽  
Leike Zhang ◽  
Shiliang Li ◽  
Yuan Sun ◽  
Minyi Ding ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Ebola Virus ◽  
De Novo ◽  
Rna Viruses ◽  
Direct Acting Antiviral ◽  
Novel Coronavirus ◽  
Direct Acting ◽  
Viral Mutagenesis

AbstractEmerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

scholarly journals Targeting the DEAD-box RNA Helicase eIF4A with Rocaglates - A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

2021 ◽  
Author(s):  
Gaspar Taroncher-Oldenburg ◽  
Christin Müller ◽  
Wiebke Obermann ◽  
John Ziebuhr ◽  
Roland K. Hartmann ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Rna Viruses ◽  
Rna Virus ◽  
Rna Helicase ◽  
Inhibitory Effect ◽  
Viral Mrnas ◽  
Eukaryotic Translation ◽  
Dead Box ◽  
A Minor ◽  
The Impact

The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5’UTRs onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5´UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad-spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

scholarly journals 3D8, a nucleic acid-hydrolyzing scFv, confers antiviral activity against SARS-CoV-2 and multiple coronaviruses in vitro

2020 ◽  
Author(s):  
Gunsup Lee ◽  
Shailesh Budhathoki ◽  
Hyeok Soon Choi ◽  
Kwang-ji Oh ◽  
Geum-Young Lee ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Therapeutic Effects ◽  
List Type ◽  
Single Chain ◽  
Diarrhea Virus ◽  
Antiviral Effects ◽  
3D8 Scfv

AbstractThe current pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a critical public health threat worldwide. Coronaviruses (subfamily Orthocoronavirinae, family Coronaviridae, order Nidovirales) are a group of enveloped positive-sense single-stranded RNA viruses. Six pathogenic human coronaviruses, likely zoonotic viruses, cause the common cold in humans. A new emerging coronavirus, SARS-CoV-2, become a crucial etiology for the Coronavirus-induced disease 19 (COVID-19). However, effective therapeutics and vaccines against multiple coronaviruses remain unavailable. This study aimed to investigate an antiviral molecule, single chain variable fragment (scFv), against SARS-CoV-2 and other coronaviruses. 3D8, a recombinant scFv, exhibits broad-spectrum antiviral activity against DNA and RNA viruses owing to its nucleic acid-hydrolyzing property. Here, we report that 3D8 scFv inhibited the replication of SARS-CoV-2, human coronavirus OC43 (HCoV-OC43), and porcine epidemic diarrhea virus (PEDV). Our results revealed the prophylactic and therapeutic effects of 3D8 scFv against SARS-CoV-2 in Vero E6 cells. Immunoblot and plaque assays showed the absence of coronavirus nucleoproteins and infectious particles in 3D8 scFv-treated cells, respectively. In addition, we observed the antiviral effects of 3D8 against HCoV-OC43 and PEDV. In conclusion, this study provides insights into the broad-spectrum antiviral agent of 3D8 scFv; thus, it could be considered a potential antiviral countermeasure against SARS-CoV-2 and zoonotic coronaviruses.Key points (Main message)3D8, a nucleic acid-hydrolyzing scFv, exhibits potent prophylactic and therapeutic antiviral effects on SARS-CoV-2.3D8 exhibits broad-spectrum antiviral activity against multiple coronaviruses: hCoV OC43 and PEDV.3D8 potentially degrades viral RNA.

Role of GS-5734 (Remdesivir) in inhibiting SARS-CoV and MERS-CoV: The expected role of GS-5734 (Remdesivir) in COVID-19 (2019-nCoV) - VYTR hypothesis.

2020 ◽  
Vol 11 (SPL1) ◽  
Author(s):  
Vityala Yethindra
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Human Body ◽  
Broad Spectrum ◽  
Rna Synthesis ◽  
Rna Viruses ◽  
Improved Outcomes ◽  
The Family

Coronaviruses (CoVs) are enveloped RNA viruses related to the family Coronaviridae, the order Nirdovales, and observed in humans and other mammals. In December 2019, many pneumonia cases reported by patients with unknown causes, mainly associated with seafood and wet animal market in Wuhan, China, and where clinically resembled viral pneumonia. At present, there is no existence of antiviral drugs for the treatment of CoV infections. The results of our study are GS-5734 strongly inhibits SARS-CoV and MERS-CoV in HAE cells, GS-5734 inhibits CoVs at early stages in replication by inhibiting viral RNA synthesis, the absence of ExoN-mediated proofreading in viruses sensitive to treatment with GS-5734. Protease inhibitors can show improved outcomes in some coronaviruses, but mostly 99% of protease inhibitors bind to proteins present in the human body, and only 1% attacks on existed viruses. The expected role of GS-5734 (Remdesivir) in the 2019-nCoV - VYTR hypothesis explained. As broad-spectrum drugs are capable of inhibiting CoV infections, GS-5734 is a broad-spectrum drug and may show inhibition on CoV infections and 2019-nCoV. GS-5734 will show desired results regarding antiviral activity against 2019-nCoV as it showed potent antiviral activity in other CoVs. More clinical trials and experiments needed to prove that GS-5734 (Remdesivir) is a potential and effective drug to treat 2019-nCoV.

scholarly journals A computational framework of host-based drug repositioning for broad-spectrum antivirals against RNA viruses

iScience ◽  
2021 ◽  
Vol 24 (3) ◽  
pp. 102148
Author(s):  
Zexu Li ◽  
Yingjia Yao ◽  
Xiaolong Cheng ◽  
Qing Chen ◽  
Wenchang Zhao ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Rna Viruses ◽  
Drug Repositioning ◽  
Computational Framework

scholarly journals 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication

Science ◽  
2022 ◽  
Vol 375 (6577) ◽  
pp. 161-167
Author(s):  
Julien Sourimant ◽  
Carolin M. Lieber ◽  
Megha Aggarwal ◽  
Robert M. Cox ◽  
Josef D. Wolf ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Severe Acute Respiratory Syndrome ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Emerging Pathogens ◽  
Primary Indication ◽  
Syncytial Virus ◽  
Derivatives Of

Preparing antiviral defenses Antiviral drugs are an important tool in the battle against COVID-19. Both remdesivir and molnupiravir, which target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase, were first developed against other RNA viruses. This highlights the importance of broad-spectrum antivirals that can be rapidly deployed against related emerging pathogens. Sourimant et al . used respiratory syncytial virus (RSV) as a primary indication in identifying further drugs that target the polymerase enzyme of RNA viruses. The authors explored derivatives of molnupiravir and identified 4′ fluorouridine (EIDD-2749) as an inhibitor of the polymerase of RSV and SARS-CoV-2. This drug can be delivered orally and was effective against RSV in mice and SARS-CoV-2 in ferrets. —VV

scholarly journals Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

2015 ◽  
Vol 89 (7) ◽  
pp. 3584-3597 ◽  
Author(s):  
Matthew D. Pauly ◽  
Adam S. Lauring
Keyword(s):  
Influenza Virus ◽  
Mutation Rate ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Nucleoside Analogs ◽  
High Mutation Rate ◽  
Induced Mutations ◽  
Genetic Barrier ◽  
Defective Interfering Particles ◽  
Lethal Mutagenesis

ABSTRACTLethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus.IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation.

scholarly journals Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

2020 ◽  
Author(s):  
Einat. B. Vitner ◽  
Roy Avraham ◽  
Hagit Achdout ◽  
Hadas Tamir ◽  
Avi Agami ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Cell Membranes ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Drugs ◽  
Membrane Dynamics ◽  
Biologically Active ◽  
Phase Iii ◽  
Glucosylceramide Synthase

AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.One Sentence SummaryAn analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.

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