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.

中文翻译：

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长链脂肪酰基辅酶A通过靶向结合病毒颗粒的脂蛋白来抑制丙型肝炎病毒感染。

丙型肝炎病毒（HCV）是慢性肝炎和晚期肝病的主要原因。成熟的HCV病毒体被宿主衍生的脂蛋白结合。HCV疫苗的缺乏保证了抗病毒治疗在全球消灭丙型肝炎中的重要作用。尽管直接作用抗病毒药（DAA）取代了基于干扰素的治疗，并显着提高了治愈率，但仍存在抗病毒的病毒变体DAA，HCV基因型/亚型特异性疗效以及DAA的高昂成本提出了新颖且负担得起的治疗方案。在这项研究中，我们确定了长链脂肪酰基辅酶A（LCFA-CoA）通过靶向成熟的HCV结合的脂蛋白对1-6型HCV感染的抗病毒作用，表明抗病毒的新机制不同于目标主机代理或DAA使用的那些。我们发现，LCFA-CoA的抗病毒活性依赖于长链饱和脂肪酸和CoA基团，并在与聚乙二醇化干扰素或DAA结合时得到增强。重要的是，我们证明了LCFA-CoA有效抑制了带有DAA抗性突变的HCV变异体的感染。机理研究表明，LCFA-CoA专门取消了附着和结合步骤，并且还抑制了细胞间的病毒传播。LCFA-CoA靶向成熟的HCV结合脂蛋白，但不靶向载脂蛋白B或E。此外，LCFA-CoA还可以抑制登革热病毒的感染。我们的发现表明，LCFA-CoA可以作为HCV的补充疗法，尤其是对于DAA耐药的HCV变异体。在一起