Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP

Abstract

Enteroviruses, e.g., polio-, coxsackie-and rhinoviruses, constitute a large genus within the Picornaviridae family of positive-strand RNA viruses and include many important pathogens linked to a variety of acute and chronic diseases. Despite their huge medical and economic impact, no approved antiviral therapy is yet available. Recently, the oxysterol-binding protein (OSBP) was implicated as a host factor for enterovirus replication. Here, we investigated the antiviral activity of the natural compound OSW-1, a ligand of OSBP that is under investigation as an anti-cancer drug. OSW-1 potently inhibited the replication of all enteroviruses tested, with IC50 values in the low nanomolar range, acted at the genome replication stage and was effective in all tested cell types of three different species. Importantly, OSBP overexpression rescued viral replication, demonstrating that the antiviral effect of OSW-1 is due to targeting OSBP. Together, we here report the anti-enterovirus activity of the natural anti-cancer compound OSW-1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Enteroviruses form a large genus belonging to the Picornaviridae family of positive-strand RNA viruses [(+)RNA] and include important human pathogens. Enteroviral infections have been implicated in a number of acute and chronic diseases, ranging from poliomyelitis (poliovirus), meningoencephalitis and myocarditis (coxsackieviruses and echoviruses), and common cold to asthma exacerbation and chronic obstructive pulmonary disease (rhinoviruses). Poliovirus is the only member of the genus for which an efficient vaccine is available and no antiviral therapy is currently approved for treating enteroviral infections. OSW-1 is a natural compound extracted from the bulbs of the plant Ornithogalum saundersiae that has been studied mainly for its anti-cancer activity. Burgett et al. (2011) identified OSBP as a high-affinity target of OSW-1 using affinity chromatography and demonstrated that OSW-1 exerts its anti-cancer activity via OSBP.In this study, we investigated the antiviral activity of OSW-1. We assessed the effect of OSW-1 on a single-round of infection of HeLa or Buffalo Green Monkey (BGM) kidney cells by viruses from different species in the Enterovirus genus, i.e., enterovirus 71 (EV71, enterovirus A species), coxsackievirus A21 (CVA21, enterovirus C species), human rhinovirus 2 (HRV2, rhinovirus A species) and human rhinovirus 14 (HRV-14, rhinovirus B species). All enteroviruses tested were sensitive to OSW-1, with IC50 values ranging between 2.4 and 9.4 nM ( Fig. 1A-E). Cell viability assays performed in parallel revealed no cytotoxicity (CC50 > 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 ...

Fat(al) attraction: Picornaviruses Usurp Lipid Transfer at Membrane Contact Sites to Create Replication Organelles

“…Similar to the physiological role of OSBP, enteroviruses exploit the PI4KIIIb-PI4P-OSBP pathway to import cholesterol into their ROs [59][60][61]. Pharmacological inhibition of this pathway by targeting either PI4P production or OSBP-mediated lipid shuttling efficiently impaired enterovirus replication [23,36,[59][60][61][62][63][64]. The observation that replication is hampered when PI4P transported to the ER is not hydrolyzed upon knockdown of Sac1 [23,60] underscores the importance of the cholesterol/PI4P-counterflux for enterovirus replication.…”

“…Little is known about the host protein and lipid requirements of picornaviruses from other genera. Studies with inhibitors of PI4Ks and OSBP suggest that members of the genera Aphthovirus (e.g., equine rhinitis A virus, a close relative of foot-and-mouth disease virus) and Parechovirus do not rely on PI4K/OSBP functions [61,62,78]. Whether these or other picornaviruses co-opt cholesterol/PI4P, either via MCSs or via alternative mechanisms, or have evolved to depend on other machineries to establish their ROs remains to be determined.…”

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].…”

Synthesis, antiviral activity and structure–activity relationship of 1-(1-aryl-4,5-dihydro-1H-imidazoline)-3-chlorosulfonylureas and products of their cyclization

“…Among the tested compounds, sophocarpinol exerted the most promising activity against not only CVB3 but also CVB1, CVB2, CVB5 and CVB6 with IC 50 ranging from 0.62 to 3.63 mM (SI from 46 to 275), indicating a broad-spectrum anti-CVB activity constituent amentoflavone also exhibit anti-CVB3 activity, both in vitro by preventing cytopathic effect formation in HEp-2 cells and in vivo by reducing mean viral titres in the heart and kidneys as well as mortality of CVB3 infected mice 11 . It was recently reported that, oxysterol-binding protein (OSBP), a PI4P-binding protein that shuttles cholesterol between membrane compartments, is implicated as another host factor for enterovirus replication 12 . OSW-1 (3b,16b,17a-trihydroxycholest-5-en-22-…”

“…-O-acetyl-a-arabinopyranoside, a natural compound extracted from the bulbs of the Ornithogalum saundersiae, and itraconazole, a well-known antifungal agent, are inhibitors of viral RNA replication by targeting oxysterol-binding protein (OSBP) and can be potentially used as broad-spectrum inhibitors of enteroviruses 12,13 . In this study, we present the evaluation of antiviral activity of N-substituted derivatives of 1-arylimidazolidyn-2-ylideneurea against the SV-1 14,15 and CVB3.…”