scholarly journals Iminosugar antivirals: the therapeutic sweet spot

2017 ◽  
Vol 45 (2) ◽  
pp. 571-582 ◽  
Author(s):  
Dominic S. Alonzi ◽  
Kathryn A. Scott ◽  
Raymond A. Dwek ◽  
Nicole Zitzmann
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Antiviral Activity ◽  
Broad Spectrum ◽  
Antiviral Effect ◽  
Sweet Spot ◽  
Future Prospects ◽  
Wide Range ◽  
Viral Glycoproteins ◽  
Endoplasmic Reticulum Protein

Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein folding cycle. Viral glycoproteins are thus prevented from interacting with the protein-folding machinery leading to misfolding and an antiviral effect against a wide range of different viral families. As iminosugars target host enzymes, they should be refractory to mutations in the virus. Iminosugars therefore have great potential for development as broad-spectrum antiviral therapeutics. We outline the mechanism giving rise to the antiviral activity of iminosugars, the current progress in the development of iminosugar antivirals and future prospects for this field.

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.

scholarly journals Antidepressant Sertraline is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry Through Neutralization of Endolysosomal Acidification

2021 ◽  
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs to treat EV71 infections. In this study, we conducted an antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be relieved greatly by exposing virus-infected cells to extracellular low-pH culture media. Together, we have identified an FDA-approved antidepressant with the new indication for the broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

scholarly journals Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State

2016 ◽  
Vol 60 (8) ◽  
pp. 4552-4562 ◽  
Author(s):  
Dong-Hoon Chung ◽  
Jennifer E. Golden ◽  
Robert S. Adcock ◽  
Chad E. Schroeder ◽  
Yong-Kyu Chu ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Cell Lines ◽  
Broad Spectrum ◽  
Antiviral Effect ◽  
Mouse Cell ◽  
Molecular Probe ◽  
Antiviral Compound ◽  
Antiviral State ◽  
Type 1 Interferons

ABSTRACTViral emergence and reemergence underscore the importance of developing efficacious, broad-spectrum antivirals. Here, we report the discovery of tetrahydrobenzothiazole-based compound 1, a novel, broad-spectrum antiviral lead that was optimized from a hit compound derived from a cytopathic effect (CPE)-based antiviral screen using Venezuelan equine encephalitis virus. Compound 1 showed antiviral activity against a broad range of RNA viruses, including alphaviruses, flaviviruses, influenza virus, and ebolavirus. Mechanism-of-action studies with metabolomics and molecular approaches revealed that the compound inhibits host pyrimidine synthesis and establishes an antiviral state by inducing a variety of interferon-stimulated genes (ISGs). Notably, the induction of the ISGs by compound 1 was independent of the production of type 1 interferons. The antiviral activity of compound 1 was cell type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. Herein, we disclose tetrahydrobenzothiazole compound 1 as a novel lead for the development of a broad-spectrum, antiviral therapeutic and as a molecular probe to study the mechanism of the induction of ISGs that are independent of type 1 interferons.

scholarly journals In Vitro Antiviral Activity of a Series of Wild Berry Fruit Extracts against Representatives of Picorna-, Orthomyxo- and Paramyxoviridae

2014 ◽  
Vol 9 (1) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Lubomira Nikolaeva-Glomb ◽  
Luchia Mukova ◽  
Nadya Nikolova ◽  
Ilian Badjakov ◽  
Ivayla Dincheva ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Influenza A ◽  
Antiviral Effect ◽  
Influenza Virus A ◽  
Methanol Extracts ◽  
Wide Range ◽  
Berry Fruits ◽  
Wild Berries

Wild berry species are known to exhibit a wide range of pharmacological activities. They have long been traditionally applied for their antiseptic, antimicrobial, cardioprotective and antioxidant properties. The aim of the present study is to reveal the potential for selective antiviral activity of total methanol extracts, as well as that of the anthocyanins and the non-anthocyanins from the following wild berries picked in Bulgaria: strawberry ( Fragaria vesca L.) and raspberry ( Rubus idaeus L.) of the Rosaceae plant family, and bilberry ( Vaccinium myrtillis L.) and lingonberry ( Vaccinium vitis-idaea L) of the Ericaceae. The antiviral effect has been tested against viruses that are important human pathogens and for which chemotherapy and/or chemoprophylaxis is indicated, namely poliovirus type 1 (PV-1) and coxsackievirus B1 (CV-B1) from the Picornaviridae virus family, human respiratory syncytial virus A2 (HRSV-A2) from the Paramyxoviridae and influenza virus A/H3N2 of Orthomyxoviridae. Wild berry fruits are freeze-dried and ground, then total methanol extracts are prepared. Further the extracts are fractioned by solid phase extraction and the non-anthocyanin and anthocyanin fractions are eluted. The in vitro antiviral effect is examined by the virus cytopathic effect (CPE) inhibition test. The results reveal that the total extracts of all tested berry fruits inhibit the replication of CV-B1 and influenza A virus. CV-B1 is inhibited to the highest degree by both bilberry and strawberry, as well as by lingonberry total extracts, and influenza A by bilberry and strawberry extracts. Anthocyanin fractions of all wild berries strongly inhibit the replication of influenza virus A/H3N2. Given the obtained results it is concluded that wild berry species are a valuable resource of antiviral substances and the present study should serve as a basis for further detailed research on the matter.

scholarly journals Antidepressant Sertraline Is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry through Neutralization of Endolysosomal Acidification

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

Synthetic Substrates for an Endoplasmic Reticulum Protein-Folding Sensor, UDP-Glucose: Glycoprotein Glucosyltransferase

2005 ◽  
Vol 117 (48) ◽  
pp. 8164-8168 ◽  
Author(s):  
Kiichiro Totani ◽  
Yoshito Ihara ◽  
Ichiro Matsuo ◽  
Hiroyuki Koshino ◽  
Yukishige Ito
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Endoplasmic Reticulum Protein

Synthetic Substrates for an Endoplasmic Reticulum Protein-Folding Sensor, UDP-Glucose: Glycoprotein Glucosyltransferase

2005 ◽  
Vol 44 (48) ◽  
pp. 7950-7954 ◽  
Author(s):  
Kiichiro Totani ◽  
Yoshito Ihara ◽  
Ichiro Matsuo ◽  
Hiroyuki Koshino ◽  
Yukishige Ito
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Endoplasmic Reticulum Protein
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