Small molecule scavenger receptor BI antagonists are potent HCV entry inhibitors

Syder, Andrew J.; Lee, Haekyung; Zeisel, Mirjam B.; Grove, Joe; Soulier, Eric; Macdonald, James E.; Chow, Stephine; Chang, Julia W.; Baumert, Thomas F.; McKeating, Jane A.; McKelvy, Jeffrey F.; Wong‐Staal, Flossie

doi:10.1016/j.jhep.2010.06.024

Cited by 130 publications

(111 citation statements)

References 49 publications

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“…The published in vitro data indicate up to 90% inhibition, which is likely less than what can be achieved with oxLDL. 20 Given its chemical complexity and potential involvement in the pathogenesis of atherosclerosis, oxLDL is an unlikely therapeutic lead compound. However, a smaller chemically defined compound that mimics its anti-HCV mechanism of action would be an attractive lead.…”

Section: Discussionmentioning

confidence: 99%

“…5,9,17,18 Animal data indicate that SR-BI is also important for HCV infection in vivo, 19 and an inhibitor of HCV/SR-BI interaction is the only HCVentry inhibitor currently in clinical trials. 20 Recent work has suggested that SR-BI fulfils at least two distinct functions during viral entry: one related to initial attachment and another during post-binding. 5,21,22 Among SR-BI ligands, HDL has a modest enhancing effect on HCV entry, 23 whereas oxLDL has been found to be a strong inhibitor.…”

mentioning

confidence: 99%

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Characterization of the inhibition of hepatitis C virus entry by In vitro –generated and patient-derived oxidized low-density lipoprotein

et al. 2013

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Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture-grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro-generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. Conclusion: oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry. (HEPATOLOGY 2013;57:1716-1724 C hronic hepatitis C virus (HCV) infection affects an estimated 160 million people worldwide. 1 Chronic HCV is a frequent cause of end-stageliver diseases (ESLDs) and hepatocellular carcinoma as well as a common indication for liver transplantation (LT). Treatment remains problematic because of side effects and high cost. A particular problem is graft reinfection that occurs immediately after LT for HCVassociated ESLD and often leads to transplant hepatitis and graft loss. 2 The HCV replication cycle is intricately linked to host lipid metabolism. 3 The production of infectious viral particles is dependent on the cellular very-lowdensity lipoprotein (VLDL) assembly machinery, and

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of the inhibition of hepatitis C virus entry by In vitro –generated and patient-derived oxidized low-density lipoprotein

et al. 2013

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“…Moreover, physiological SR-BI ligands modulate HCV infection (Bartosch et al 2005;Voisset et al 2005;von Hahn et al 2006), suggesting the existence of a complex interplay between lipoproteins (not only HDL), SR-BI and HCV envelope glycoproteins for HCV entry. Earlier studies using small molecule inhibitors indicated a role for SR-BI lipid transfer function in HCV infection and HDL-mediated entry enhancement (Bartosch et al 2003;Dreux et al 2009;Syder et al 2011;Voisset et al 2005). A human anti-SR-BI mAb has been reported to inhibit HDL binding, to interfere with cholesterol efflux, and to decrease cell culture-derived HCV (HCVcc) entry during attachment steps without having a relevant impact on SR-BI-mediated post-binding steps (Catanese et al 2007(Catanese et al , 2010.…”

Section: Hcv Infectionmentioning

confidence: 99%

HDL in Infectious Diseases and Sepsis

Pirillo

Catapano

Norata

2014

Handbook of Experimental Pharmacology

180

163

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“…Reporter protein Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

Section: Xmentioning

confidence: 99%

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

Section: Epha2mentioning

confidence: 99%