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Lipid Droplet Isolation for Quantitative Mass Spectrometry Analysis
Published on: April 17, 2017
Long-chain fatty acyl-coenzyme A suppresses hepatitis C virus infection by targeting virion-bound lipoproteins
Xinlei Li1, Jinqian Li2, Yetong Feng2
1State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.
Insights
Long-chain fatty acyl-coenzyme A (LCFA-CoA) shows antiviral effects against Hepatitis C virus (HCV) genotypes 1-6 by targeting lipoproteins on mature virions. This novel approach is effective against DAA-resistant HCV and dengue virus.
Area of Science:
- Virology
- Biochemistry
- Drug Discovery
Background:
- Hepatitis C virus (HCV) causes chronic liver disease, necessitating effective antiviral treatments due to the absence of a vaccine.
- Direct-acting antivirals (DAAs) have improved cure rates but face challenges from resistant viral variants, genotype-specific efficacy, and high costs.
- Novel therapeutic strategies are needed to combat HCV, especially drug-resistant strains.
Purpose of the Study:
- To investigate the antiviral effects of long-chain fatty acyl-coenzyme A (LCFA-CoA) against Hepatitis C virus (HCV) infections.
- To elucidate the mechanism of action of LCFA-CoA, distinguishing it from host-targeting agents and DAAs.
- To evaluate LCFA-CoA's efficacy against DAA-resistant HCV variants and other viruses.
Main Methods:
- Screening for antiviral activity of LCFA-CoA against HCV genotypes 1-6.
- Investigating the structural components of LCFA-CoA essential for antiviral activity.
- Assessing the synergistic effects of LCFA-CoA with pegylated-interferon and DAAs.
- Evaluating LCFA-CoA's impact on viral attachment, binding, and cell-to-cell transmission.
- Testing LCFA-CoA against DAA-resistant HCV variants and dengue virus.
Main Results:
- LCFA-CoA demonstrated broad-spectrum antiviral activity against HCV genotypes 1-6 by targeting mature HCV-bound lipoproteins.
- Antiviral activity was dependent on the long-chain saturated fatty acid and CoA group, with enhanced effects when combined with existing therapies.
- LCFA-CoA effectively inhibited DAA-resistant HCV variants by blocking viral attachment, binding, and cell-to-cell transmission.
- The compound also showed inhibitory effects against dengue virus infection.
Conclusions:
- LCFA-CoA represents a novel class of antiviral agents targeting components of mature HCV virions.
- Its unique mechanism of action, distinct from host-targeting agents and DAAs, makes it a promising candidate for treating DAA-resistant HCV.
- LCFA-CoA could serve as a valuable supplement to current HCV therapies, offering a new strategy for viral elimination.
Abstract:
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and end-stage liver diseases. Mature HCV virions are bound by host-derived lipoproteins. Lack of an HCV vaccine warrants a major role of antiviral treatment in the global elimination of hepatitis C. Although direct-acting antivirals (DAAs) are replacing the interferon-based treatment and have dramatically improved the cure rate, the presence of viral variants resistant to DAAs, HCV genotype/subtype-specific efficacy, and high cost of DAAs argue novel and affordable regimens. In this study, we identified the antiviral effects of long-chain fatty acyl-coenzyme A (LCFA-CoA) against the infections of HCV genotypes 1-6 through targeting mature HCV-bound lipoproteins, suggesting novel mechanism(s) of antiviral different from those used by host-targeting agents or DAAs. We found that the antiviral activity of LCFA-CoA relied on the long-chain saturated fatty acid and the CoA group, and was enhanced when combined with pegylated-interferon or DAAs. Importantly, we demonstrated that LCFA-CoA efficiently inhibited the infection of HCV variants carrying DAA-resistant mutations. The mechanistic study revealed that LCFA-CoA specifically abolished the attachment and binding steps and also inhibited the cell-to-cell viral transmission. LCFA-CoA targeted mature HCV-bound lipoproteins, but not apolipoproteins B or E. In addition, LCFA-CoA could also inhibit the infection of the dengue virus. Our findings suggest that LCFA-CoA could potentially serve as a supplement HCV therapy, particularly for the DAA-resistant HCV variants. Taken together, LCFA-CoA may be further developed to be a novel class of antivirals with mechanism(s), different from host-targeting agents or DAAs, of targeting the components associated with mature HCV virions.
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