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

Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(5), P. e202302453 - e202302453

Published: Feb. 22, 2024

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

Language: Английский

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Lymphatic-derived oxysterols promote anti-tumor immunity and response to immunotherapy in melanoma

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 31, 2025

Language: Английский

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Lipid-targeting antiviral strategies: current state and future perspectives

Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106103 - 106103

Published: Feb. 1, 2025

Language: Английский

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

Archives of Microbiology, Journal Year: 2023, Volume and Issue: 205(4)

Published: March 7, 2023

Language: Английский

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Cholesterol 25-hydroxylase suppresses avian reovirus replication by its enzymatic product 25-hydroxycholesterol

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: June 29, 2023

Avian reovirus (ARV) causing viral arthritis/tenosynovitis and enteritis in domestic fowl has significantly threatened on the poultry industry worldwide. ARV is a non-enveloped fusogenic virus that belongs to Reoviridae family. Previous research revealed cellular cholesterol lipid rafts essential for replication. It been reported 25-hydroxylase (CH25H) its product 25-hydroxycholesterol (25HC) have antiviral activities against enveloped viruses. However, few studies characterized association of viruses with CH25H role regulation In this study, expression chicken (chCH25H) was found be upregulated ARV-infected cells at early stage infection. The results overexpression knockdown assays chCH25H significant effect Furthermore, 25HC treatment inhibited replication dose-dependent manner both entry post-entry stages, mutant lacking hydroxylase activity failed inhibit These indicate CH25H, depending enzyme activity, exerts via synthesis 25HC. addition, we produced by inhibits delaying kinetics uncoating, blocks cell–cell membrane fusion induced p10 protein ARV. Altogether, our findings showed as natural host restriction factor, possessed targeting syncytium formation, through an activity-dependent way. This study may provide new insights into development broad-spectrum therapies.

Language: Английский

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

Microorganisms, Journal Year: 2023, Volume and Issue: 11(8), P. 2075 - 2075

Published: Aug. 12, 2023

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

Language: Английский

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Inhibition Mechanism of SARS-CoV-2 Infection by a Cholesterol Derivative, Nat-20(S)-yne

Biological and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 47(5), P. 930 - 940

Published: April 30, 2024

The coronavirus disease 2019 (COVID-19) is caused by the etiological agent severe acute respiratory syndrome 2 (SARS-CoV-2). COVID-19, with recurrent epidemics of new variants SARS-CoV-2, remains a global public health problem, and antivirals are still required. Some cholesterol derivatives, such as 25-hydroxycholesterol, known to have antiviral activity against wide range enveloped non-enveloped viruses, including SARS-CoV-2. At entry step SARS-CoV-2 infection, viral envelope fuses host membrane dependent spike (S) glycoproteins. From screening we found compound 26,27-dinorcholest-5-en-24-yne-3β,20-diol (Nat-20(S)-yne) that inhibited S protein-dependent fusion in syncytium formation assay. Nat-20(S)-yne exhibited inhibitory activities pseudovirus intact infection dose-dependent manner. Among inhibition was stronger delta Wuhan strains, which predominantly invade into cells via at plasma membrane, than omicron strains. interaction between receptor-binding domain proteins receptor ACE2 not affected Nat-20(S)-yne. Unlike regulates various steps metabolism, only de novo biosynthesis. As result, content substantially decreased Nat-20(S)-yne-treated cells, leading infection. having mechanism action may be potential therapeutic candidate for COVID-19.

Language: Английский

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Acetyl-L-carnitine ameliorates atherosclerosis in LDLR−/− mice by modulating cholesterol metabolism through SREBP2-dependent cholesterol biosynthesis

Frontiers in Nutrition, Journal Year: 2024, Volume and Issue: 11

Published: Dec. 16, 2024

Background Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality globally. Hypercholesterolemia accelerates atherosclerotic development and an independent modifiable risk factor for ASCVD. Reducing cholesterol levels effective in preventing Acetyl-L-carnitine (ALC) endogenous molecule that plays a primary role energy metabolism; however, its effect on metabolism remains unclear. Methods We collected plasma samples clinical data from 494 individuals with hyperlipidemia. Targeted metabolomics were used to measure ALC explore association levels. Additionally, we explored effects murine hypercholesterolemia model. An LDLR −/− mouse-based model was established investigate roles progression. Results Plasma concentrations significantly negatively correlated total (TC) ( r = −0.43, p < 0.0001) low-density lipoprotein (LDL-C; −0.53, 0.0001). Incorporating into diet reduced TC LDL-C levels, downregulated genes involved synthesis, such as sterol regulatory element-binding protein 2 (SREBP2) 3-hydroxy-3-methyl-glutaryl-CoA reductase, upregulated receptor expression. supplementation substantially lowered inhibited atherosclerosis mice. Conclusion plaque formation by lowering via suppression SREBP2-mediated thus suggesting potential therapeutic target

Language: Английский

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Phenotypic switch of vascular smooth muscle cells in COVID‐19: Role of cholesterol, calcium, and phosphate

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(12)

Published: Aug. 26, 2024

Abstract Although the novel coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), primarily manifests as distress, its impact on cardiovascular system is also notable. Studies reveal that COVID‐19 patients often suffer from certain vascular diseases, partly attributed to increased proliferation or altered phenotype of smooth muscle cells (VSMCs). association between and VSMCs recognized, precise mechanism underlying SARS‐CoV‐2's influence VSMC remains largely under‐reviewed. In this context, while there a consistent body literature dissecting effect system, few reports delve into potential role switching in pathophysiology associated with molecular mechanisms involved therein. This review dissects critiques link VSMCs, particular attention pathways involving cholesterol, calcium, phosphate. These underpin interaction virus VSMCs. Such promotes proliferation, eventually potentiates calcification well worsens prognosis COVID‐19.

Language: Английский

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Inhibition of Marek’s Disease Virus Replication and Spread by 25-hydroxycholesterol and 27-hydroxycholesterol In Vitro

Viruses, Journal Year: 2023, Volume and Issue: 15(8), P. 1652 - 1652

Published: July 29, 2023

Marek’s disease virus (MDV) causes a deadly lymphoproliferative in chickens, resulting huge economic losses the poultry industry. It has been suggested that MDV suppresses induction of type I interferons and thus escapes immune control. Cholesterol 25-hydroxylase (CH25H), gene encodes an enzyme catalyses cholesterol to 25-hydroxycholesterol (25-HC), is interferon-stimulating (ISG) known exert antiviral activities. Other oxysterols, such as 27-hydroxycholesterols (27-HC), have also shown activities, 27-HC synthesised by catalysis via cytochrome P450 oxidase sterol 27-hydroxylase A1 (CYP27A1). At 24 h post infection (hpi), stimulated interferon (IFN-α) response, which was significantly reduced at 48 72 hpi, detected using luciferase assay for chicken IFNs. Then, RT-PCR, we demonstrated IFN upregulates CH25H CYP27A1 genes embryo fibroblast (CEF) cells. In parallel, our results demonstrate moderate transient upregulation hpi 72hpi MDV-infected CEF A significant reduction titer plaque sizes observed CEFs treated with 25-HC or vitro, standard MDV. Taken together, suggest may be useful agents control replication spread.

Language: Английский

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