Studies in the antiviral molecular mechanisms of 25-hydroxycholesterol: Disturbing cholesterol homeostasis and post-translational modification of proteins

Mao, Shijie; Ren, Jie; Xu, Ying; Lin, Jidong; Pan, Chuqiao; Meng, Yu

doi:10.1016/j.ejphar.2022.175033

Cited by 8 publications

(11 citation statements)

References 105 publications

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“…The molecule 25-hydroxycholesterol (25HC) has been recognized for its potential to inhibit the entry and replication of various coronaviruses, including PEDV and SARS-CoV-2. This inhibitory activity is mainly achieved by interfering with viral fusion and entry into host cells and disrupting viral protein maturation [ 42 , 43 , 44 , 45 , 46 ]. To further investigate the effect of 25HC on pseudovirus rVSV-ΔG-EGFP-S infection, we pretreated Huh7 cells with 25HC at concentrations of 50 μM and 100 μM for 2 h and subsequently infected these cells with rVSV-ΔG-EGFP-S virus.…”

Section: Resultsmentioning

confidence: 99%

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

Luo,

Lv,

et al. 2023

Microorganisms

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The porcine epidemic diarrhea virus (PEDV) is a highly contagious and virulent enteric coronavirus that causes severe enteric disease in pigs worldwide. PEDV infection causes profound diarrhea, vomiting, and dehydration in pigs of all ages, resulting in high mortality rates, particularly among neonatal piglets. The spike glycoprotein (S) of PEDV plays a crucial role in binding to the host cell receptor and facilitating fusion between the viral and host membranes. Pseudotyped viral particles featuring the PEDV S protein are valuable tools for investigating virus entry, identifying neutralizing antibodies, and developing small molecules to impede virus replication. In this study, we used a codon-optimized PEDV S protein to generate recombinant pseudotyped vesicular stomatitis virus (VSV) particles (rVSV-ΔG-EGFP-S). The full-length S protein was efficiently incorporated into VSV particles. The S protein pseudotyped VSV exhibited infectivity towards permissive cell lines of PEDV. Moreover, we identified a new permissive cell line, JHH7, which showed robust support for PEDV replication. In contrast to the SARS-CoV-2 spike protein, the removal of amino acids from the cytoplasmic tail resulted in reduced efficiency of viral pseudotyping. Furthermore, we demonstrated that 25-hydroxycholesterol inhibited rVSV-ΔG-EGFP-S entry, while human APN facilitated rVSV-ΔG-EGFP-S entry through the use of ANPEP knockout Huh7 cells. Finally, by transducing swine intestinal organoids with the rVSV-ΔG-EGFP-S virus, we observed efficient infection of the swine intestinal organoids by the PEDV spike-pseudotyped VSV. Our work offers valuable tools for studying the cellular entry of PEDV and developing interventions to curb its transmission.

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Section: Resultsmentioning

confidence: 99%

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

Luo,

Lv,

et al. 2023

Microorganisms

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“…However, designing and identifying active compounds focusing on these components can be challenging, due to their similarity to the host cell membrane (Sousa et al 2020 ). Interestingly, the compound 25-hydroxycholesterol (25HC), a reactive oxysterol catalyzed by cholesterol-25-hydroxylase, is a promising molecule that can interact with lipids on viral membrane, and demonstrated broad-spectrum antiviral activity, low toxicity, and ability to reduce viremia and protect embryonic mice against ZIKV in vivo (Li et al 2017 ; Mao et al 2022 ). In this context, molecules focused on interacting with cholesterol could be employed to drug development against MAYV.…”

Section: Molecular Target To Drug Development Against Mayvmentioning

confidence: 99%

An update on the development of antiviral against Mayaro virus: from molecules to potential viral targets

et al. 2023

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Mayaro virus (MAYV), first isolated in 1954 in Trinidad and Tobago islands, is the causative agent of Mayaro fever, a disease characterized by fever, rashes, headaches, myalgia, and arthralgia. The infection can progress to a chronic condition in over 50% of cases, with persistent arthralgia, which can lead to the disability of the infected individuals. MAYV is mainly transmitted through the bite of the female Haemagogus spp. mosquito genus. However, studies demonstrate that Aedes aegypti is also a vector, contributing to the spread of MAYV beyond endemic areas, given the vast geographical distribution of the mosquito. Besides, the similarity of antigenic sites with other Alphavirus complicates the diagnoses of MAYV, contributing to underreporting of the disease. Nowadays, there are no antiviral drugs available to treat infected patients, being the clinical management based on analgesics and non-steroidal anti-inflammatory drugs. In this context, this review aims to summarize compounds that have demonstrated antiviral activity against MAYV in vitro, as well as discuss the potentiality of viral proteins as targets for the development of antiviral drugs against MAYV. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential anti-MAYV drug candidates. Supplementary Information The online version contains supplementary material available at 10.1007/s00203-023-03441-y.

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“…Besides cholesterol-depleting agents, oxysterols such as 25-hydroxycholesterol can also reduce the availability of cell surface cholesterol, with inhibitory consequences for viral infectivity (reviewed in Mao et al [2022] ). In Calu-3a cells, Caco-2 cells, and lung organoids, 25-hydroxycholesterol interfered with the fusion of SARS-CoV-2 with the cell surface ( Wang et al, 2020b ), most likely because of the transfer of cell surface cholesterol to lipid droplets.…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, in HEK293 (human embryonic kidney) cells, 25-hydroxycholesterol accumulated in LE/Lys and blocked cholesterol export from this compartment, which appeared to inhibit SARS-CoV-2 spike protein-mediated fusion with the LE/Lys membrane ( Zang et al, 2020 ). Notably, cholesterol-25-hydroxylase, which generates 25-hydroxycholesterol, is stimulated by interferon, up-regulated by SARS-CoV-2 infection and in COVID-19 patients, indicating that the generation of this oxysterol is part of the innate immune response to combat SARS-CoV-2 propagation ( Mao et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

Grewal,

Nguyen,

Buechler

2024

Life Sci. Alliance

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The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities to lower SARS-CoV-2 infection rates and improve COVID-19 outcome. This includes cellular cholesterol, which is critical for viral spike proteins to capture the host machinery for SARS-CoV-2 cell entry. Once endocytosed, exit of SARS-CoV-2 from the late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release of new viral particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, and ezetimibe have revealed potential to protect against COVID-19. In addition, pharmacological inhibition of cholesterol exiting late endosomes/lysosomes identified drug candidates, including antifungals, to block SARS-CoV-2 infection. This review describes the multiple roles of cholesterol at the cell surface and endolysosomes for SARS-CoV-2 entry and the potential of drugs targeting cholesterol homeostasis to reduce SARS-CoV-2 infectivity and COVID-19 disease severity.

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Studies in the antiviral molecular mechanisms of 25-hydroxycholesterol: Disturbing cholesterol homeostasis and post-translational modification of proteins

Cited by 8 publications

References 105 publications

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

Establishment of Replication Deficient Vesicular Stomatitis Virus for Studies of PEDV Spike-Mediated Cell Entry and Its Inhibition

An update on the development of antiviral against Mayaro virus: from molecules to potential viral targets

Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

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