Novel activities of safe-in-human broad-spectrum antiviral agents

doi:10.1016/j.antiviral.2018.04.016

Review

. 2018 Jun:154:174-182.

doi: 10.1016/j.antiviral.2018.04.016. Epub 2018 Apr 23.

Novel activities of safe-in-human broad-spectrum antiviral agents

Aleksandr Ianevski¹, Eva Zusinaite², Suvi Kuivanen³, Mårten Strand⁴, Hilde Lysvand⁵, Mona Teppor⁶, Laura Kakkola⁷, Henrik Paavilainen⁸, Mira Laajala⁹, Hannimari Kallio-Kokko¹⁰, Miia Valkonen¹¹, Anu Kantele¹², Kaidi Telling¹³, Irja Lutsar¹⁴, Pille Letjuka¹⁵, Natalja Metelitsa¹⁶, Valentyn Oksenych¹⁷, Magnar Bjørås¹⁸, Svein Arne Nordbø¹⁹, Uga Dumpis²⁰, Astra Vitkauskiene²¹, Christina Öhrmalm²², Kåre Bondeson²³, Anders Bergqvist²⁴, Tero Aittokallio²⁵, Rebecca J Cox²⁶, Magnus Evander²⁷, Veijo Hukkanen²⁸, Varpu Marjomaki²⁹, Ilkka Julkunen³⁰, Olli Vapalahti³¹, Tanel Tenson³², Andres Merits³³, Denis Kainov³⁴

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway. Electronic address: aleksandr.ianevski@helsinki.fi.
² Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: eva.zusinaite@gmail.com.
³ Department of Virology, University of Helsinki, Helsinki 00014, Finland. Electronic address: suvi.kuivanen@helsinki.fi.
⁴ Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: marten.strand@umu.se.
⁵ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: hilde.lysvand@ntnu.no.
⁶ Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: mona.teppor@gmail.com.
⁷ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: laura.kakkola@utu.fi.
⁸ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: hojpaa@utu.fi.
⁹ Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: mira.a.laajala@jyu.fi.
¹⁰ Department of Virology and Immunology, University of Helsinki, Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: hannimari.kallio-kokko@hus.fi.
¹¹ Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: miia.valkonen@hus.fi.
¹² Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: anu.kantele@helsinki.fi.
¹³ Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: kaidi.telling@ut.ee.
¹⁴ Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: irja.lutsar@ut.ee.
¹⁵ Narva Haigla, Narva 20104, Estonia. Electronic address: ellipellip@mail.ru.
¹⁶ Narva Haigla, Narva 20104, Estonia. Electronic address: nmetelitsa@gmail.com.
¹⁷ St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Trondheim 7006, Norway. Electronic address: valentyn.oksenych@ntnu.no.
¹⁸ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: magnar.bjoras@ntnu.no.
¹⁹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Medical Microbiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7006, Norway. Electronic address: svein.a.nordbo@ntnu.no.
²⁰ Pauls Stradins Clinical University Hospital, Riga 1002, Latvia. Electronic address: uga.dumpis@gmail.com.
²¹ Department of Laboratory Medicine, Lithuanian University of Health Science, Kaunas 44307, Lithuania. Electronic address: astra.vitkauskiene@kaunoklinikos.lt.
²² Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: christina.ohrmalm@akademiska.se.
²³ Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: kare.bondeson@akademiska.se.
²⁴ Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: anders.bergqvist@akademiska.se.
²⁵ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Department of Mathematics and Statistics, University of Turku, Turku 20014, Finland. Electronic address: tero.aittokallio@fimm.fi.
²⁶ Influenza Centre, Department of Clinical Science, University of Bergen, Bergen 5021, Norway. Electronic address: rebecca.cox@uib.no.
²⁷ Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: magnus.evander@umu.se.
²⁸ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: veijo.hukkanen@utu.fi.
²⁹ Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: varpu.s.marjomaki@jyu.fi.
³⁰ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: ilkka.julkunen@utu.fi.
³¹ Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki 00014, Finland. Electronic address: olli.vapalahti@helsinki.fi.
³² Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: tanel.tenson@ut.ee.
³³ Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: andres.merits@ut.ee.
³⁴ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway; Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: denis.kainov@helsinki.fi.

PMID: 29698664
PMCID: PMC7113852
DOI: 10.1016/j.antiviral.2018.04.016

Review

Novel activities of safe-in-human broad-spectrum antiviral agents

Aleksandr Ianevski et al. Antiviral Res. 2018 Jun.

. 2018 Jun:154:174-182.

doi: 10.1016/j.antiviral.2018.04.016. Epub 2018 Apr 23.

Authors

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway. Electronic address: aleksandr.ianevski@helsinki.fi.
² Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: eva.zusinaite@gmail.com.
³ Department of Virology, University of Helsinki, Helsinki 00014, Finland. Electronic address: suvi.kuivanen@helsinki.fi.
⁴ Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: marten.strand@umu.se.
⁵ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: hilde.lysvand@ntnu.no.
⁶ Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: mona.teppor@gmail.com.
⁷ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: laura.kakkola@utu.fi.
⁸ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: hojpaa@utu.fi.
⁹ Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: mira.a.laajala@jyu.fi.
¹⁰ Department of Virology and Immunology, University of Helsinki, Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: hannimari.kallio-kokko@hus.fi.
¹¹ Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: miia.valkonen@hus.fi.
¹² Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: anu.kantele@helsinki.fi.
¹³ Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: kaidi.telling@ut.ee.
¹⁴ Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: irja.lutsar@ut.ee.
¹⁵ Narva Haigla, Narva 20104, Estonia. Electronic address: ellipellip@mail.ru.
¹⁶ Narva Haigla, Narva 20104, Estonia. Electronic address: nmetelitsa@gmail.com.
¹⁷ St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Trondheim 7006, Norway. Electronic address: valentyn.oksenych@ntnu.no.
¹⁸ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: magnar.bjoras@ntnu.no.
¹⁹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Medical Microbiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7006, Norway. Electronic address: svein.a.nordbo@ntnu.no.
²⁰ Pauls Stradins Clinical University Hospital, Riga 1002, Latvia. Electronic address: uga.dumpis@gmail.com.
²¹ Department of Laboratory Medicine, Lithuanian University of Health Science, Kaunas 44307, Lithuania. Electronic address: astra.vitkauskiene@kaunoklinikos.lt.
²² Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: christina.ohrmalm@akademiska.se.
²³ Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: kare.bondeson@akademiska.se.
²⁴ Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: anders.bergqvist@akademiska.se.
²⁵ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Department of Mathematics and Statistics, University of Turku, Turku 20014, Finland. Electronic address: tero.aittokallio@fimm.fi.
²⁶ Influenza Centre, Department of Clinical Science, University of Bergen, Bergen 5021, Norway. Electronic address: rebecca.cox@uib.no.
²⁷ Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: magnus.evander@umu.se.
²⁸ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: veijo.hukkanen@utu.fi.
²⁹ Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: varpu.s.marjomaki@jyu.fi.
³⁰ Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: ilkka.julkunen@utu.fi.
³¹ Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki 00014, Finland. Electronic address: olli.vapalahti@helsinki.fi.
³² Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: tanel.tenson@ut.ee.
³³ Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: andres.merits@ut.ee.
³⁴ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway; Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: denis.kainov@helsinki.fi.

PMID: 29698664
PMCID: PMC7113852
DOI: 10.1016/j.antiviral.2018.04.016

Abstract

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.

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Figures

**Fig. 1**
Eye diagram showing approved drugs for the treatment of viral diseases in human (left), their viral and host targets (right) as well as viruses they inhibit (middle). Broad-spectrum antiviral drugs are shown in bold.

**Fig. 2**
Eye diagram showing antiviral agents in clinical trials (left), their viral and host targets (right), as well as viruses they inhibit (middle). Broad-spectrum antiviral agents are shown in bold.

**Fig. 3**
Eye diagram showing approved drugs for the treatment of non-viral diseases (left), which also possess antiviral activity, their viral and host targets (right), as well as viruses they inhibit (middle). Broad-spectrum antiviral agents are shown in bold.

**Fig. 4**
The interaction network between 55 viruses and 59 BSAs, which are safe in man. Drug-like shapes represent antiviral agents. Blue spheres represent viruses. The diameter of spheres corresponds to the number of interactions between the viruses and the drugs. Novel interactions between BSAs and viruses are shown in red, validated – in blue, and known - in grey. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

See this image and copyright information in PMC

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References

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[1] Al-Bari M.A.A. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 2017;5 - PMC - PubMed

[2] Al-Bari M.A.A. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 2017;5 - PMC - PubMed

[3] Andrei G., Topalis D., De Schutter T., Snoeck R. Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia. Antivir. Res. 2015;114:21–46. - PubMed

[4] Andrei G., Topalis D., De Schutter T., Snoeck R. Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia. Antivir. Res. 2015;114:21–46. - PubMed

[5] Barrows N.J., Campos R.K., Powell S.T., Prasanth K.R., Schott-Lerner G., Soto-Acosta R., Galarza-Munoz G., McGrath E.L., Urrabaz-Garza R., Gao J., Wu P., Menon R., Saade G., Fernandez-Salas I., Rossi S.L., Vasilakis N., Routh A., Bradrick S.S., Garcia-Blanco M.A. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe. 2016;20:259–270. - PMC - PubMed

[6] Barrows N.J., Campos R.K., Powell S.T., Prasanth K.R., Schott-Lerner G., Soto-Acosta R., Galarza-Munoz G., McGrath E.L., Urrabaz-Garza R., Gao J., Wu P., Menon R., Saade G., Fernandez-Salas I., Rossi S.L., Vasilakis N., Routh A., Bradrick S.S., Garcia-Blanco M.A. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe. 2016;20:259–270. - PMC - PubMed

[7] Beach L.B., Rawson J.M., Kim B., Patterson S.E., Mansky L.M. Novel inhibitors of human immunodeficiency virus type 2 infectivity. J. Gen. Virol. 2014;95:2778–2783. - PMC - PubMed

[8] Beach L.B., Rawson J.M., Kim B., Patterson S.E., Mansky L.M. Novel inhibitors of human immunodeficiency virus type 2 infectivity. J. Gen. Virol. 2014;95:2778–2783. - PMC - PubMed

[9] Bekerman E., Einav S. Infectious disease. Combating emerging viral threats. Science. 2015;348:282–283. - PMC - PubMed

[10] Bekerman E., Einav S. Infectious disease. Combating emerging viral threats. Science. 2015;348:282–283. - PMC - PubMed

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Novel activities of safe-in-human broad-spectrum antiviral agents

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Novel activities of safe-in-human broad-spectrum antiviral agents

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