Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment
Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment
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DOI：
10.1016/j.antiviral.2016.07.003
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发表时间：
2016-08-01
影响因子：
7.6
通讯作者：
Hijikata, Makoto
中科院分区：
文献类型：
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作者：
Nio, Yasunori;Hasegawa, Hikari;Hijikata, Makoto
近年来，直接抗丙型肝炎病毒药物已被开发为高效抗丙型肝炎病毒药物。然而，出现对直接抗病毒药物具有耐药性的病毒是一个尚未解决的问题。抑制耐药病毒出现的策略之一是使用抑制宿主因素的药物，与直接抗病毒药物联合使用。宿主因素有助于促进丙型肝炎病毒的增殖。据报道，复制复合体存在于细胞的膜室中。因此，脂代谢调节剂是调节病毒组装和丙型肝炎病毒复制的很好候选药物。最近的研究表明，硬脂酰辅酶A脱饱和酶(SCD)是合成长链单不饱和脂肪酸(LCMUFA)的酶，是决定丙型肝炎病毒复制效率的关键因素。全身暴露于SCD-1抑制剂会对眼睛和皮肤产生一些副作用。因此，系统的SCD-1抑制剂被认为不适合丙型肝炎的治疗。为了避免全身性SCD-1抑制剂的副作用，合成了肝脏特异性的SCD-1抑制剂MK8245，在糖尿病模型小鼠中显示了降血糖作用，没有副作用。在测量MK8245耐受性的第一阶段临床研究中，没有显著副作用的报道(ClinicalTrials.gov标识：NCT00790556)。因此，我们认为肝脏特异性SCD-1抑制剂将适合丙型肝炎病毒感染患者。用重组丙型肝炎病毒培养系统对MK8245进行鉴定。考虑到目前丙型肝炎病毒的治疗，为了避免出现直接抗病毒药物耐药病毒，直接抗病毒药物和宿主靶向药物的联合治疗将是最佳选择。基于这一观点，我们证实了MK8245‘S在目前的直接抗病毒药物和干扰素治疗中的抗丙型肝炎病毒的添加或协同作用。结果表明，MK8245是一种抗丙型肝炎病毒多药联合治疗的选择，出现耐药丙型肝炎病毒的风险较低，且没有明显的副作用。(C)2016爱思唯尔B.V.保留所有权利。
Recently, direct antiviral agents against hepatitis C virus (HCV) infection have been developed as highly effective anti-HCV drugs. However, the appearance of resistant viruses against direct anti-viral agents is an unsolved problem. One of the strategies considered to suppress the emergence of the drug-resistant viruses is to use drugs inhibiting the host factor, which contributes to HCV proliferation, in combination with direct anti-viral agents. The replication complex was reported to be present in the membranous compartment in the cells. Thus, lipid metabolism modulators are good candidates to regulate virus assembly and HCV replication. Recent studies have shown that stearoyl-CoA desaturase (SCD), an enzyme for long-chain mono-unsaturated fatty acid (LCMUFA) synthesis, is a key factor that defines HCV replication efficiency. Systemic exposure to SCD-1 inhibor induces some side effects in the eyes and skin. Thus, systemic SCD-1 inhibitors are considered inappropriate for HCV therapy. To avoid the side effects of systemic SCD-1 inhibitors, the liver-specific SCD-1 inhibitor, MK8245, was synthesized; it showed antidiabetic effects in diabetic model mice with no side effects. In the phase 1 clinical study on measurement of MK8245 tolerability, no significant side effects were reported (ClinicalTrials.gov Identifier: NCT00790556). Therefore, we thought liver-specific SCD-1 inhibitors would be suitable agents for HCV-infected patients. MK8245 was evaluated using recombinant HCV culture systems. Considering current HCV treatments, to avoid the emergence of direct anti-viral agents-resistant viruses, combination therapy with direct anti-viral agents and host-targeted agents would be optimal. With this viewpoint, we confirmed MK8245's additive or synergistic anti-HCV effects on current direct anti-viral agents and interferon-alpha therapy. The results suggest that MK8245 is an option for anti-HCV multi-drug therapy with a low risk of emergence of drug-resistant HCV without significant side effects. (C) 2016 Elsevier B.V. All rights reserved.