Exploring the Potential of Iminosugars as Antivirals for Crimean-Congo Haemorrhagic Fever Virus, Using the Surrogate Hazara Virus: Liquid-Chromatography-Based Mapping of Viral N-Glycosylation and In Vitro Antiviral Assays

Beatrice E Tyrrell; Abhinav Kumar; Bevin Gangadharan; Dominic Alonzi; Juliane Brun; Michelle Hill; Tehmina Bharucha; Andrew Bosworth; Victoria Graham; Stuart Dowall; Joanna L Miller; Nicole Zitzmann

doi:10.3390/pathogens12030399

Exploring the Potential of Iminosugars as Antivirals for Crimean-Congo Haemorrhagic Fever Virus, Using the Surrogate Hazara Virus: Liquid-Chromatography-Based Mapping of Viral N-Glycosylation and In Vitro Antiviral Assays

Pathogens. 2023 Mar 1;12(3):399. doi: 10.3390/pathogens12030399.

Affiliations

¹ Department of Biochemistry and Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK.
² UK Health Security Agency (UKHSA), Porton Down, Salisbury SP4 0JG, UK.

Abstract

Crimean-Congo haemorrhagic fever virus (CCHFV) is a pathogen of increasing public health concern, being a widely distributed arbovirus and the causative agent of the potentially fatal Crimean-Congo haemorrhagic fever. Hazara virus (HAZV) is a genetically and serologically related virus that has been proposed as a surrogate for antiviral and vaccine testing for CCHFV. Glycosylation analysis of HAZV has been limited; first, we confirmed for the first time the occupation of two N-glycosylation sites in the HAZV glycoprotein. Despite this, there was no apparent antiviral efficacy of a panel of iminosugars against HAZV, as determined by quantification of the total secretion and infectious virus titres produced following infection of SW13 and Vero cells. This lack of efficacy was not due to an inability of deoxynojirimycin (DNJ)-derivative iminosugars to access and inhibit endoplasmic reticulum α-glucosidases, as demonstrated by free oligosaccharide analysis in uninfected and infected SW13 and uninfected Vero cells. Even so, iminosugars may yet have potential as antivirals for CCHFV since the positions and importance of N-linked glycans may differ between the viruses, a hypothesis requiring further evaluation.

Keywords: antivirals; glycosylation; imminosugars; nairovirus; orthonairovirus; tick-borne virus.

Grants and funding

B.E.T. was supported by the Wellcome Trust [grant number 105402/Z/14/Z]. J.L.M., J.B. and B.G. were funded by the Oxford Glycobiology endowment. This work was supported by the University of Oxford and the Oxford Glycobiology endowment. T.B. was supported by the Medical Research Council [grant number MR/N013468/1]. The views in this article are those of the authors and do not necessarily represent those of the funders or employing institutes.