Abstract
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.
Highlights
Members of the family Flaviviridae are of major human health concern, and in several cases, the development of effective options for the prevention and treatment of infections caused by these viruses is urgently awaited
We show that K22 efficiently impairs the replication of Zika virus (ZIKV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and West Nile virus (WNV), as well as, to a certain extent, Usutu virus (USUV), Wesselsbron virus (WESSV), hepatitis C virus (HCV), and bovine viral diarrhea virus (BVDV)
Given our previous findings that the small-compound inhibitor K22 may interfere with conserved features of virusinduced membrane remodeling, we hypothesized that K22 might, in addition to coronaviruses and arteriviruses, impair the replication of viruses belonging to the family of Flaviviridae, such as ZIKV
Summary
Members of the family Flaviviridae are of major human health concern, and in several cases, the development of effective options for the prevention and treatment of infections caused by these viruses is urgently awaited. The Flaviviridae family comprises a wide variety of enveloped viruses possessing an RNA genome of positive polarity, and it is subdivided into four genera: Hepacivirus, Flavivirus, Pegivirus, and Pestivirus [1]. With the exception of HCV, intervention strategies against members of the family Flaviviridae are limited This emphasizes the need for the development of effective and reliable drugs and vaccines, especially in the context of newly emerging or reemerging viral infections. Given that virus-induced membrane remodeling is a conserved mechanism among virtually all positive-sense RNA viruses, it represents an attractive target for the development of panviral inhibitors effective against a wide range of viruses. It was recently reported that K22 impairs the replication of viruses in the Coronavirinae subfamily and members of the Torovirinae subfamily, such as white beam virus (WBV; genus Bafinivirus) and equine torovirus (EToV; genus Torovirus), as well as porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV), which are representative arteriviruses [13]
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