Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents

Andersen, Petter I.; Ianevski, Aleksandr; Lysvand, Hilde; Vitkauskienė, Astra; Oksenych, Valentyn; Bjørås, Magnar; Telling, Kaidi; Lutsar, Irja; Dumpis, Uga; Irie, Y.; Tenson, Tanel; Vapalahti, Olli; Kainov, Denis E.

doi:10.20944/preprints201910.0144.v5

Cited by 5 publications

(7 citation statements)

References 95 publications

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“…1). [2][3][4] In addition to the generally accepted nucleoside forms, the azoloazines themselves are relevant in the search for means of combating diseases on a global scale. Nitroazolo- [5,1-c][1,2,4]triazines and nitroazolo [1,5-a]pyrimidines, a new family of antiviral compounds has been found.…”

mentioning

confidence: 99%

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Pyrimido[1,2-a]benzimidazoles: synthesis and perspective of their pharmacological use

Fedotov

Русинов

Ulomsky

et al. 2021

Chem Heterocycl Comp

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Nitrogen-containing heterocyclic compounds are the basis of many natural and synthetic biologically active substances. 1 More than two-thirds of the known drugs used in clinical practice contain heterocyclic and, above all, nitrogen-containing fragments within their structure. Over the past decades, the chemistry of aza-heterocycles has received considerable attention due to the wide spectrum of their biological activity and numerous therapeutic applications in medicine.Of nitrogenous heterocycles, azoloazines containing fragments similar to the natural heterocycles purines and pyrimidines are currently of great practical importance. Thus, non-natural nucleosides abacavir, famciclovir, remdesivir are known, which are the products of structural modifications of all the components of the nucleotide exhibiting excellent indicators of antiviral action (Fig. 1). [2][3][4] In addition to the generally accepted nucleoside forms, the azoloazines themselves are relevant in the search for means of combating diseases on a global scale. Nitroazolo- [5,1-c][1,2,4]triazines and nitroazolo [1,5-a]pyrimidines, a new family of antiviral compounds has been found. 5 The

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mentioning

confidence: 99%

“…medication Triazavirin (2-methylsulfanyl-6-nitro [1,2,4]triazolo [5,1-c] [1,2,4]triazin-7-one sodium salt dihydrate) showed a broad spectrum of antiviral action and high efficacy. The medication protects against infection caused by influenza viruses, [6][7][8][9] ARVI, 10 tick-borne encephalitis.…”

mentioning

confidence: 99%

Pyrimido[1,2-a]benzimidazoles: synthesis and perspective of their pharmacological use

Fedotov

Русинов

Ulomsky

et al. 2021

Chem Heterocycl Comp

View full text Add to dashboard Cite

show abstract

“…A full list of genes at this threshold for Cas9 mRNA is shown in A while for core ISGs a full list is provided in Supplementary Figure 1. obtained from the broad-spectrum antiviral agents database, drugvirus.info (32).…”

Section: Study Limitationsmentioning

confidence: 99%

“…Boxes with black diagonals highlight cases where information on the activity of a given drug against a specific virus is unavailable based on previous publications in the broadspectrum anti-viral drugs database (32).…”

Section: Study Limitationsmentioning

confidence: 99%

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

Nordor¹,

Siwo²

2021

Preprint

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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.

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“…To determine broad-antiviral potential of the predicted small molecules on coronaviruses, we used public data obtained from high-throughput screens of 2000 compounds (29) and a smaller library of 290 approved drugs (30). We also obtained broad-spectrum activity data to other viruses from a recent study (28) and its associated database (drugvirus.info).…”

Section: Broad-spectrum Antiviral Analysismentioning

confidence: 99%

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

Nordor¹,

Siwo²

2020

Preprint

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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.

show abstract

Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents

Cited by 5 publications

References 95 publications

Pyrimido[1,2-a]benzimidazoles: synthesis and perspective of their pharmacological use

Pyrimido[1,2-a]benzimidazoles: synthesis and perspective of their pharmacological use

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

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

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