scholarly journals Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

2020 ◽  
Author(s):  
Akpeli V. Nordor ◽  
Geoffrey H. Siwo
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Viral Rna ◽  
Host Cells ◽  
Target Cells ◽  
Transcriptional Responses ◽  
Exogenous Rna

All RNA viruses deliver their genomes into target host cells through processes distinct from normal trafficking of cellular RNA transcripts. The delivery of viral RNA into most cells hence triggers innate antiviral defenses that recognize viral RNA as foreign. In turn, viruses have evolved mechanisms to subvert these defenses, allowing them to thrive in target cells. Therefore, drugs activating defense to foreign or exogenous RNA could serve as broad-spectrum antiviral drugs. Here we show that transcriptional signatures associated with cellular responses to the delivery of a non-viral exogenous RNA sequence into human cells predicts small molecules with broad-spectrum antiviral activity. In particular, transcriptional responses to the delivery of cas9 mRNA into human hematopoietic stem and progenitor cells (HSPCs) highly matches those triggered by small molecules with broad-spectrum antiviral activity such as emetine, homoharringtonine, pyrvinium pamoate and anisomycin, indicating that these drugs are potentially active against other RNA viruses. Furthermore, these drugs have been approved for other indications and could thereby be repurposed to novel viruses. We propose that the antiviral activity of these drugs to SARS-CoV-2 should therefore be determined as they have been shown as active against other coronaviruses including SARS-CoV and MERS-CoV. These drugs could also be explored as potential adjuvants to COVID-19 vaccines in development due to their potential effect on the innate antiviral defenses that could bolster adaptive immunity when delivered alongside vaccine antigens.

scholarly journals Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

2021 ◽  
Author(s):  
Akpeli V. Nordor ◽  
Geoffrey H. Siwo
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Viral Rna ◽  
Host Cells ◽  
Target Cells ◽  
Transcriptional Responses ◽  
Exogenous Rna

All RNA viruses deliver their genomes into target host cells through processes distinct from normal trafficking of cellular RNA transcripts. The delivery of viral RNA into most cells hence triggers innate antiviral defenses that recognize viral RNA as foreign. In turn, viruses have evolved mechanisms to subvert these defenses, allowing them to thrive in target cells. Therefore, drugs activating defense to exogenous RNA could serve as broad-spectrum antiviral drugs. Here we show that transcriptional signatures associated with cellular responses to the delivery of a non-viral exogenous RNA sequence into human cells predict small molecules with broad-spectrum antiviral activity. In particular, transcriptional responses to the delivery of Cas9 mRNA into human hematopoietic stem and progenitor cells (HSPCs) highly matches those triggered by small molecules with broad-spectrum antiviral activity such as emetine, homoharringtonine, pyrvinium pamoate and anisomycin, indicating that these drugs are potentially active against other RNA viruses. Furthermore, these drugs have been approved for other indications and could thereby be repurposed to novel viruses. We propose that the antiviral activity of these drugs to SARS-CoV-2 should therefore be determined as they have been shown as active against other coronaviruses including SARS-CoV-1 and MERS-CoV. Indeed, two of these drugs- emetine and homoharringtonine- were independently shown to inhibit SARS-CoV-2 as this article was in preparation. These drugs could also be explored as potential adjuvants to COVID-19 vaccines in development due to their potential effect on the innate antiviral defenses that could bolster adaptive immunity when delivered alongside vaccine antigens.

scholarly journals Doratoxylon apetalum, an Indigenous Medicinal Plant from Mascarene Islands, Is a Potent Inhibitor of Zika and Dengue Virus Infection in Human Cells

2019 ◽  
Vol 20 (10) ◽  
pp. 2382 ◽  
Author(s):  
Juliano G. Haddad ◽  
Andrea Cristine Koishi ◽  
Arnaud Gaudry ◽  
Claudia Nunes Duarte dos Santos ◽  
Wildriss Viranaicken ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Medicinal Plant ◽  
Dengue Virus ◽  
Denv Infection ◽  
Antiviral Drugs ◽  
Human Cells ◽  
Host Cells ◽  
Global Public Health ◽  
Denv Serotypes ◽  
Mascarene Islands

Zika virus (ZIKV) and Dengue virus (DENV) are mosquito-borne viruses of the Flavivirus genus that could cause congenital microcephaly and hemorrhage, respectively, in humans, and thus present a risk to global public health. A preventive vaccine against ZIKV remains unavailable, and no specific antiviral drugs against ZIKV and DENV are licensed. Medicinal plants may be a source of natural antiviral drugs which mostly target viral entry. In this study, we evaluate the antiviral activity of Doratoxylum apetalum, an indigenous medicinal plant from the Mascarene Islands, against ZIKV and DENV infection. Our data indicated that D. apetalum exhibited potent antiviral activity against a contemporary epidemic strain of ZIKV and clinical isolates of four DENV serotypes at non-cytotoxic concentrations in human cells. Time-of-drug-addition assays revealed that D. apetalum extract acts on ZIKV entry by preventing the internalisation of virus particles into the host cells. Our data suggest that D. apetalum-mediated ZIKV inhibition relates to virus particle inactivation. We suggest that D. apetalum could be a promising natural source for the development of potential antivirals against medically important flaviviruses.

scholarly journals Targeting the GRP78-Dependant SARS-CoV-2 Cell Entry by Peptides and Small Molecules

2020 ◽  
Vol 14 ◽  
pp. 117793222096550
Author(s):  
Loubna Allam ◽  
Fatima Ghrifi ◽  
Hakmi Mohammed ◽  
Naima El Hafidi ◽  
Rachid El Jaoudi ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Sites ◽  
Epigallocatechin Gallate ◽  
Host Cells ◽  
Spike Protein ◽  
Target Cells ◽  
Binding Affinities ◽  
Rapid Spread ◽  
Inhibitor Compounds ◽  
Potential Inhibitors

The global burden of infections and the rapid spread of viral diseases show the need for new approaches in the prevention and development of effective therapies. To this end, we aimed to explore novel inhibitor compounds that can stop replication or decrease the viral load of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there is currently no approved treatment. Besides using the angiotensin-converting enzyme (ACE2) receptor as a main gate, the CoV-2 can bind to the glucose-regulating protein 78 (GRP78) receptor to get into the cells to start an infection. Here, we report potential inhibitors comprising small molecules and peptides that could interfere with the interaction of SARS-CoV-2 and its target cells by blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. These inhibitors were discovered through an approach of in silico screening of available databases of bioactive peptides and polyphenolic compounds and the analysis of their docking modes. This process led to the selection of 9 compounds with optimal binding affinities to the target sites. The peptides (satpdb18674, satpdb18446, satpdb12488, satpdb14438, and satpdb28899) act on regions III and IV of the viral Spike protein and on its binding sites in GRP78. However, 4 polyphenols such as epigallocatechin gallate (EGCG), homoeriodictyol, isorhamnetin, and curcumin interact, in addition to the Spike protein and its binding sites in GRP78, with the ATPase domain of GRP78. Our work demonstrates that there are at least 2 approaches to block the spread of SARS-CoV-2 by preventing its fusion with the host cells via GRP78.

scholarly journals Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses and SARS-CoV-2

2020 ◽  
Author(s):  
Daniel Limonta ◽  
Lovely Dyna-Dagman ◽  
William Branton ◽  
Tadashi Makio ◽  
Richard W. Wozniak ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Present Report ◽  
Fetal Brain ◽  
Interferon Response ◽  
Brain Cells ◽  
Human Fetal Brain ◽  
Block Formation ◽  
Oligomerization Domain

ABSTRACTIn the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses and SARS-CoV-2, the causative agent of COVID-19. Another drug that inhibits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) which functions downstream of NOD2, also decreased replication of these pathogenic RNA viruses. The broad-spectrum action of nodosome targeting drugs is mediated, at least in part, by enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.

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.

scholarly journals Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses, enteroviruses and SARS-CoV-2

2021 ◽  
Author(s):  
Daniel Limonta ◽  
Lovely Dyna-Dagman ◽  
William Branton ◽  
Valeria Mancinelli ◽  
Tadashi Makio ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Present Report ◽  
Fetal Brain ◽  
Antiviral Effect ◽  
Interferon Response ◽  
Human Fetal Brain ◽  
Block Formation ◽  
Oligomerization Domain

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses, enteroviruses, and SARS-CoV-2, the causative agent of COVID-19. Another drug that inhibits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) which functions downstream of NOD2, also decreased replication of these pathogenic RNA viruses. The antiviral effect of this drug was particularly potent against enteroviruses. The broad-spectrum action of nodosome targeting drugs is mediated in part by enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.

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.

Macrodomain Binding Compound MRS 2578 Inhibits Alphavirus Replication

2021 ◽  
Author(s):  
Sari Mattila ◽  
Pirjo Merilahti ◽  
Sarah Wazir ◽  
Tania Quirin ◽  
Mirko M. Maksimainen ◽  
...  
Keyword(s):  
Semliki Forest Virus ◽  
Rna Viruses ◽  
Virus Production ◽  
Rna Replication ◽  
Viral Rna ◽  
Host Cells ◽  
Febrile Disease ◽  
Replication Stage ◽  
Replication Systems ◽  
Positive Strand Rna

Alphaviruses are positive-strand RNA viruses causing febrile disease. Macrodomain-containing proteins, involved in ADP-ribose mediated signaling, are encoded by both host cells and several virus groups, including alphaviruses. In this study, compound MRS 2578 that targets the human MacroD1 protein inhibited Semliki Forest virus production as well as viral RNA replication and replicase protein expression. The inhibitor was similarly active in alphavirus trans -replication systems, indicating that it targets the viral RNA replication stage.

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 Antiviral Effects of Plant Extracts Used in the Treatment of Important Animal Viral Diseases

2021 ◽  
Vol 11 (4) ◽  
pp. 521-533
Author(s):  
Gamil Sayed Gamil Zeedan ◽  
Abeer Mostafa Abdalhamed
Keyword(s):  
Antiviral Activity ◽  
Viral Infection ◽  
Plant Extracts ◽  
Rna Viruses ◽  
Biological Activities ◽  
Antiviral Drugs ◽  
Antiviral Compounds ◽  
Antiviral Activities

The goal of this review was to highlight some plant species that have significant antiviral activity against DNA and RNA viruses in vitro and in vivo although more research is needed to address safety issues, drug interactions, and the possibility of using them in combination with other natural products. Viral infection plays an important role in human and animal diseases. Although there have been advances in immunization and antiviral drugs, there is still a lack of protective vaccines and effective antiviral drugs in human and veterinary medicine. The lack of effective antivirals necessitates the search for new effective antiviral compounds. Plants are naturally gifted at synthesizing antiviral compounds. They are rich sources of phytochemicals with different biological activities, including antiviral activities as a result of advanced analytical chemistry, standard virus assays, and development of standardization and extraction methods. Plant extracts have a wide variety of active compounds, including flavonoids, terpenoids, lignans, sulphides, polyphenolics, coumarins, saponins, furyl compounds, alkaloids, polyines, thiophenes, proteins, and peptides. Moreover, certain volatile oils have indicated a high level of antiviral activity. Replication, assembly, and release, as well as targeting virus host-specific interactions capable of inhibiting several viruses, could help the development of broad-spectrum antivirals for the prevention and control of viral pathogens. The in vitro antiviral activities of Erythroxylum deciduum, Lacistema hasslerianum (chodat), Xylopia aromatica, Heteropteris aphrodisiaca, Acacia nilotica (gum arabic tree), Lippia graveolens (Guettarda angelica (Velvetseed), Prunus myrtifolia, and Symphyopappus plant extracts can inhibite viral replication, and interfer with the early stages of viral adsorption of DNA viruses. However, Boesenbergia rotunda plant extracts have inhibited RNA viruses. A potent anti-SARS-CoV-2 inhibitor with B. rotunda extract and panduratin A after viral infection drastically suppresses SARS-CoV-2 infectivity in Vero E6 cells.

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