Towards a broad-spectrum antiviral, the myristoyltransferase inhibitor IMP-1088 suppresses viral replication – the Yellow fever NS5 is myristoylated

Abstract

AbstractAlthough a potent Yellow fever vaccine is available since 1937, up to 200.000 severe cases are reported per year, which indicates that virus vaccines require additional support by antiviral therapies. Direct-acting antiviral drugs against severe and widespread diseases, such as DENV and Yellow fever infections with more than millions of diagnosed diseases per year, are still not available. Since antivirals’ development against neglected diseases is uneconomical, a broadspectrum antiviral compound would be of public benefit. Here, we show that IMP-1088, a recently published myristoyltransferase-1/2 inhibitor suppressing Rhino- and Polioviruses, inhibits replication of HIV-1, Yellow fever virus, Dengue virus, Vaccinia virus, CMV, and human Herpesvirus 8 in the low nanomolar range, indicating that IMP-1088 has broad-range activity against different pathogenic virus families. The inhibition relies on virally encoded myristoylation signals since Zika, Chikungunya, and Enterovirus 71 are not affected by IMP-1088. Furthermore, we show that the Yellow fever NS5 protein is myristoylated and IMP-1088 treatment of Dengue and Yellow fever infected cells leads to a re-localisation of the viral NS5 proteins.Author SummaryTreatment of viral diseases requires the development of tailored drugs specific to inhibit certain virus families. This specificity results in missing treatment options for important human pathogens such as Yellow fever and Dengue virus infection since the development is laborious and costly. Substances acting on various virus families could solve this problem. Here, we describe that IMP-1088, an inhibitor of the cellular myristoyltransferase, inhibits HIV-1, Dengue virus, Yellow fever viruses, Vaccinia virus, and Herpesviruses at low concentrations, which do not affect cell proliferation. Viruses without predicated myristoylation sites, such as Zika viruses, were not inhibited by IMP-1088. Since no experimental evidence was provided that Yellow fever virus proteins are myristoylated, we analysed the post-translational modification of Yellow fever NS5 protein. We determined the subcellular localisation to understand the mechanism of the IMP-1088 mediated suppression and could show that both the Dengue and the Yellow fever NS5 proteins are re-localised by IMP-1088 treatment.