The small compound inhibitor K22 displays broad antiviral activity against different members of the family Flaviviridae and offers potential as pan-viral inhibitor.

Garcia Nicolas, Obdulio; V'kovski, Philip; Vielle, Nathalie J.; Ebert, Nadine; Züst, R; Portmann, Jasmine; Stalder, Hanspeter; Gaschen, Véronique; Vieyres, G; Stoffel, Michael; Schweizer, Matthias; Summerfield, Artur; Engler, O; Pietschmann, T; Todt, D; Alves, Marco; Thiel, Volker; Pfänder, Stephanie (2018). The small compound inhibitor K22 displays broad antiviral activity against different members of the family Flaviviridae and offers potential as pan-viral inhibitor. Antimicrobial agents and chemotherapy, 62(11) American Society for Microbiology 10.1128/AAC.01206-18

[img]
Preview
Text
e01206-18.full.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (3MB) | Preview

The virus family Flaviviridae encompasses several viruses, including (re)emerging viruses which cause widespread morbidity and mortality throughout the world. Members of this virus family are positive-strand RNA viruses and replicate their genome in close association with reorganized intracellular host cell membrane compartments. This evolutionarily conserved strategy facilitates efficient viral genome replication and contributes to evasion from host cell cytosolic defense mechanisms. We have previously described the identification of a small-compound inhibitor, K22, which exerts a potent antiviral activity against a broad range of coronaviruses by targeting membrane-bound viral RNA replication. To analyze the antiviral spectrum of this inhibitor, we assessed the inhibitory potential of K22 against several members of the Flaviviridae family, including the reemerging Zika virus (ZIKV). We show that ZIKV is strongly affected by K22. Time-of-addition experiments revealed that K22 acts during a postentry phase of the ZIKV life cycle, and combination regimens of K22 together with ribavirin (RBV) or interferon alpha (IFN-α) further increased the extent of viral inhibition. Ultrastructural electron microscopy studies revealed severe alterations of ZIKV-induced intracellular replication compartments upon infection of K22-treated cells. Importantly, the antiviral activity of K22 was demonstrated against several other members of the Flaviviridae family. It is tempting to speculate that K22 exerts its broad antiviral activity against several positive-strand RNA viruses via a similar mechanism and thereby represents an attractive candidate for development as a panviral inhibitor.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Veterinary Anatomy
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)
09 Interdisciplinary Units > Microscopy Imaging Center MIC

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Garcia Nicolas, Obdulio; V'kovski, Philip; Vielle, Nathalie Jane; Ebert, Nadine; Portmann, Jasmine; Stalder, Hanspeter; Gaschen, Véronique; Stoffel, Michael Hubert; Schweizer, Matthias; Summerfield, Artur; Alves, Marco; Thiel, Volker Earl and Pfänder, Stephanie

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology

ISSN:

0066-4804

Publisher:

American Society for Microbiology

Language:

English

Submitter:

Philip V'kovski

Date Deposited:

21 Nov 2018 15:24

Last Modified:

11 Jan 2019 13:31

Publisher DOI:

10.1128/AAC.01206-18

PubMed ID:

30181371

BORIS DOI:

10.7892/boris.121443

URI:

https://boris.unibe.ch/id/eprint/121443

Actions (login required)

Edit item Edit item
Provide Feedback