Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307

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.

Host lipidome analysis during rhinovirus replication in HBECs identifies potential therapeutic targets

“…VAP-A binds OSBPs, which are a family of lipid transfer proteins that control cholesterol/PI4P exchange at ER-Golgi membrane contact sites and also bind Arf1. OSBPs are also targeted by certain anti-picornaviral drugs (4,6,47), providing further evidence for the requirement for lipid homeostasis at the ER/Golgi interface for viral replication. Additionally, the anti-viral effector protein, interferon-inducible transmembrane protein 3, interacts with VAP-A and prevents its association with OSBP, thereby disrupting intracellular cholesterol homeostasis and inhibiting viral entry (48).…”

WITHDRAWN: The Fundamental And Pathological Importance Of Oxysterol Binding Protein And Its Related Proteins

“…A role for OSBP in the supply of cholesterol to replication organelles has also been shown in poliovirus, dengue (107), picornavirus (108) and encephalomyocarditis virus infections (109). OSBP has since been identified as the drug target of the anti-enteroviral compounds TTP-8307 and itraconazole (110,111). The role of OSBP in viral replication also explains the antiviral properties of the OSBP/OSBP2 inhibitor OSW-1, which is better known for its anti-tumorigenic effects (112).…”

Direct-acting antivirals and host-targeting strategies to combat enterovirus infections

“…OSBP is recruited to ROs through the PI4KB-mediated increase in PI4P and its lipid shuttling activity is essential for viral genome replication. Other OSBP inhibitors (e.g., 25-hydroxycholesterol, AN-12-H5, T-00127-HEV2, TTP-8307, and the natural compound OSW-1) also impaired enterovirus replication [56,[63][64][65]. In a rhinovirus mouse model, prophylactic intranasal treatment with itraconazole reduced viral titers and pathology, raising expectations for topically applied itraconazole to prevent or treat common colds [66].…”