Abstract
The genus Enterovirus (e.g. poliovirus, coxsackievirus, rhinovirus) of the Picornaviridae family of positive-strand RNA viruses includes many important pathogens linked to a range of acute and chronic diseases for which no approved antiviral therapy is available. Targeting a step in the life cycle that is highly conserved provides an attractive strategy for developing broad-range inhibitors of enterovirus infection. A step that is currently explored as a target for the development of antivirals is the formation of replication organelles, which support replication of the viral genome. To build replication organelles, enteroviruses rewire cellular machinery and hijack lipid homeostasis pathways. For example, enteroviruses exploit the PI4KIIIβ-PI4P-OSBP pathway to direct cholesterol to replication organelles. Here, we uncover that TTP-8307, a known enterovirus replication inhibitor, acts through the PI4KIIIβ-PI4P-OSBP pathway by directly inhibiting OSBP activity. However, despite a shared mechanism of TTP-8307 with established OSBP inhibitors (itraconazole and OSW-1), we identify a number of notable differences between these compounds. The antiviral activity of TTP-8307 extends to other viruses that require OSBP, namely the picornavirus encephalomyocarditis virus and the flavivirus hepatitis C virus.
Highlights
Enteroviruses constitute a large genus in the Picornaviridae family of positive-strand RNA [(+)RNA]viruses, including important human pathogens that are associated with a range of acute and chronic diseases
Like the established oxysterol-binding protein (OSBP) inhibitor ITZ and in contrast to BF738735 (Strating et al, 2015), treatment with TTP-8307 did not reduce but instead mildly enhanced the perinuclear FAPP1-PH-GFP signal (Fig. 1B). This indicates that TTP-8307 does not inhibit phosphatidylinositol 4-phosphate (PI4P) production by PI4KIIIb and acts at another stage of the PI4KIIIb-PI4P-OSBP pathway
OSBP overexpression does not rescue virus replication in the presence of TTP-8307 We previously demonstrated that OSBP overexpression restores coxsackievirus B3 (CVB3) replication in the presence of the OSBP inhibitors ITZ and OSW-1, but not in the presence of PI4KIIIb inhibitors (Albulescu et al, 2015a; Strating et al, 2015)
Summary
Enteroviruses constitute a large genus in the Picornaviridae family of positive-strand RNA [(+)RNA]viruses, including important human pathogens (e.g. polioviruses, coxsackieviruses, echoviruses, rhinoviruses) that are associated with a range of acute and chronic diseases. Targeting a highly conserved step in the replication cycle is considered an attractive strategy to combat a broad range of enteroviruses. One such step is viral genome replication, a process takes place on membranous structures, so-called replication organelles [recently reviewed by Van der Schaar, et al (2016)]. Compounds that target this pathway, like PI4KIIIb inhibitors (e.g. enviroxime, BF738735, GW5074, PIK93, T-00127-HEV1) and OSBP inhibitors (e.g. 25-hydroxycholesterol [25OHC], T-00127-HEV2, AN-12-H5, itraconazole [ITZ], OSW-1), efficiently disrupt enterovirus replication (Albulescu et al, 2015a; Arita et al, 2011; Arita et al, 2013; Hsu et al, 2010; Strating et al, 2015; van der Schaar et al, 2013; van der Schaar et al, 2012)
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