Abstract
Dengue virus (DENV) is the etiologic agent for dengue fever, for which there is no approved vaccine or specific anti-viral drug. As a remedy for this, we explored the use of compounds that interfere with the action of required host factors and describe here the characterization of a kinase inhibitor (SFV785), which has selective effects on NTRK1 and MAPKAPK5 kinase activity, and anti-viral activity on Hepatitis C, DENV and yellow fever viruses. SFV785 inhibited DENV propagation without inhibiting DENV RNA synthesis or translation. The compound did not cause any changes in the cellular distribution of non-structural 3, a protein critical for DENV RNA synthesis, but altered the distribution of the structural envelope protein from a reticulate network to enlarged discrete vesicles, which altered the co-localization with the DENV replication complex. Ultrastructural electron microscopy analyses of DENV-infected SFV785-treated cells showed the presence of viral particles that were distinctly different from viable enveloped virions within enlarged ER cisternae. These viral particles were devoid of the dense nucleocapsid. The secretion of the viral particles was not inhibited by SFV785, however a reduction in the amount of secreted infectious virions, DENV RNA and capsid were observed. Collectively, these observations suggest that SFV785 inhibited the recruitment and assembly of the nucleocapsid in specific ER compartments during the DENV assembly process and hence the production of infectious DENV. SFV785 and derivative compounds could be useful biochemical probes to explore the DENV lifecycle and could also represent a new class of anti-virals.
Highlights
Dengue fever, the most prevalent arthropod-borne viral diseases of humans [1], can be caused by four Dengue virus (DENV) serotypes (DENV-1, dengue virus 2 New Guinea C strain (DENV-2), DENV-3, and DENV-4)
Quantitative analysis of non-structural 3 protein (NS3) expression showed that about 7% of the cells were infected in the presence 10 mM suppressor of flaviviridae-785 (SFV785), whereas about 60% of the cells were infected in the presence of SRPIN614, or vehicle (0.1% DMSO) (Figure 2B)
Our findings support the action of SFV785 at the assembly stage of infectious DENV within the endoplasmic reticulum (ER)
Summary
The most prevalent arthropod-borne viral diseases of humans [1], can be caused by four DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4). There is no available effective antiviral therapy for DENV infection and the development of a dengue vaccine is challenging because of the need to induce long-lasting protection against all four DENV serotypes simultaneously. Virus assembly occurs within ER vesicles that are in close proximity to these pores, with the ensuing accumulation of these viruses in dilated ER compartments proximal to the Golgi. All these processes occur within compartments of one ER-derived network [5,6]. Virions are subsequently released from cells via the host cell secretory machinery These different stages of DENV replication require complex interaction between viral and cellular factors [7,8]. Small molecules that target critical host factors could be useful for the biochemical characterization of host–virus interactions and are anti-DENV drug candidates
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