Fatty acid synthase and stearoyl-CoA desaturase-1 are conserved druggable cofactors of Old World Alphavirus genome replication.,Antiviral Research

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Fatty acid synthase and stearoyl-CoA desaturase-1 are conserved druggable cofactors of Old World Alphavirus genome replication.
Antiviral Research ( IF 4.5 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.antiviral.2019.104642
William Bakhache ₁ , Aymeric Neyret ₁ , Joe McKellar ₁ , Camille Clop ₁ , Eric Bernard ₁ , James Weger-Lucarelli ₂ , Laurence Briant ₁

Affiliation

Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne RNA virus that causes epidemics of debilitating disease in tropical and sub-tropical regions with autochtonous transmission in regions with temperate climate. Currently, there is no licensed vaccine or specific antiviral drug available against CHIKV infection. In this study, we examine the role, in the CHIKV viral cycle, of fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1), two key lipogenic enzymes required for fatty acid production and early desaturation. We show that both enzymes and their upstream regulator PI3K are required for optimal CHIKV infection. We demonstrate that pharmacologic manipulation of FASN or SCD1 enzymatic activity by non-toxic concentrations of cerulenin or CAY10566 decreases CHIKV genome replication. Interestingly, a similar inhibitory effect was also obtained with Orlistat, an FDA-approved anti-obesity drug that targets FASN activity. These drugs were also effective against Mayaro virus (MAYV), an under-studied arthritogenic Old world Alphavirus endemic in South American countries with potential risk of emergence, urbanization and dispersion to other regions. Altogether, our results identify FASN and SCD1 as conserved druggable cofactors of Alphavirus genome replication and support the broad-spectrum activity of drugs targeting the host fatty acids metabolism.

中文翻译：

脂肪酸合酶和硬脂酰-CoA去饱和酶-1是旧世界Alphavirus基因组复制的保守药物辅助因子。

基孔肯雅病毒（CHIKV）是一种迅速出现的蚊媒RNA病毒，可在热带和亚热带地区引起衰弱性疾病的流行，并在温带气候地区自发传播。当前，没有针对CHIKV感染的许可疫苗或特定抗病毒药物。在这项研究中，我们检查了脂肪酸合酶（FASN）和硬脂酰辅酶A去饱和酶（SCD1）在CHIKV病毒循环中的作用，这两种脂肪酸是脂肪产生和早期去饱和的关键脂肪酶。我们表明，两种酶及其上游调节剂PI3K是最佳CHIKV感染所必需的。我们证明通过无毒浓度的铜蓝蛋白或CAY10566的FASN或SCD1酶活性的药理学操纵会降低CHIKV基因组的复制。有趣的是，FDA批准的靶向FASN活性的抗肥胖药Orlistat也获得了相似的抑制作用。这些药物还可以有效抵抗Mayaro病毒（MAYV），该病毒在南美国家是一种被研究不足的致关节炎的旧世界Alphavirus流行病，具有出现，城市化和扩散到其他地区的潜在风险。总而言之，我们的结果确定FASN和SCD1是Alphavirus基因组复制的保守可药用辅因子，并支持靶向宿主脂肪酸代谢的药物的广谱活性。城市化和分散到其他地区。总而言之，我们的结果确定FASN和SCD1是Alphavirus基因组复制的保守可药用辅因子，并支持靶向宿主脂肪酸代谢的药物的广谱活性。城市化和分散到其他地区。总而言之，我们的结果确定FASN和SCD1是Alphavirus基因组复制的保守可药用辅因子，并支持靶向宿主脂肪酸代谢的药物的广谱活性。

更新日期：2019-10-31

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