Discovery and development of safe-in-man broad-spectrum antiviral agents

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Highlights

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We reviewed the discovery and development process of broad-spectrum antiviral agents.
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We summarized the information on 120 safe-in-man agents in a freely accessible database.
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Further studies will increase the number of broad-spectrum antivirals, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections.

Abstract

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database ( https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Miao Xu, Emily M Lee, Zhexing Wen … (2016)

In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

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Are animal models predictive for humans?

Niall Shanks, Ray Greek, Jean Greek (2009)

It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics.

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Author and article information

Contributors

Denis E. Kainov

Journal

Journal ID (nlm-ta): Int J Infect Dis

Journal ID (iso-abbrev): Int. J. Infect. Dis

Title: International Journal of Infectious Diseases

Publisher: The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

ISSN (Print): 1201-9712

ISSN (Electronic): 1878-3511

Publication date PMC-release: 17 February 2020

Publication date (Print): April 2020

Publication date (Electronic): 17 February 2020

Volume: 93

Pages: 268-276

Affiliations

[a ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7028 Trondheim, Norway

[b ]Department of Laboratory Medicine, Lithuanian University of Health Science, 44307 Kaunas, Lithuania

[c ]Institute of Technology, University of Tartu, 50090 Tartu, Estonia

[d ]Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia

[e ]Latvian Biomedical Research and Study Centre, Riga 1067, Latvia

[f ]Helsinki University Hospital (HUS) and University of Helsinki, Helsinki 00290, Finland

[g ]Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland

Author notes

[* ]Corresponding author at: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7028 Trondheim, Norway. denis.kainov@ 123456ntnu.no

[1]

Contributed equally.

Article

Publisher ID: S1201-9712(20)30076-X

DOI: 10.1016/j.ijid.2020.02.018

PMC ID: 7128205

PubMed ID: 32081774

SO-VID: bd97ad55-37e0-47f6-9a7a-3944840bc830

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 24 January 2020

Date revision received : 7 February 2020

Date accepted : 11 February 2020

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Discovery and development of safe-in-man broad-spectrum antiviral agents

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Zika Virus

Most cited references 79

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Are animal models predictive for humans?

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Cited by 88

Most referenced authors 4,856