病毒开放阅读框架3蛋白与宿主肿瘤易感基因101之间相互作用

StephenW

Potent Inhibition of Hepatitis E Virus Release by a Cyclic Peptide Inhibitor of the Interaction between Viral Open Reading Frame 3 Protein and Host Tumor Susceptibility Gene 101
Saumya Anang, Nidhi Kaushik, Smita Hingane, Anita Kumari, Jyoti Gupta, Shailendra Asthana, Shalimar, Baibaswata Nayak, C. T. Ranjith-Kumar, Milan Surjit
J.-H. James Ou, Editor
DOI: 10.1128/JVI.00684-18

    ArticleFigures & DataInfo & Metrics
    PDF

ABSTRACT

Hepatitis E virus (HEV) generally causes self-limiting acute viral hepatitis in normal individuals. It causes a more severe disease in immunocompromised persons and pregnant women. Due to the lack of an efficient cell culture system or animal model, the life cycle of the virus is understudied, few antiviral targets are known, and very few antiviral candidates against HEV infection have been identified. Inhibition of virus release is one possible antiviral development strategy, which limits the spread of the virus. Previous studies have demonstrated the essential role of the interaction between the PSAP motif of the viral open reading frame 3 protein (ORF3-PSAP) and the UEV domain of the host tumor susceptibility gene 101 (TSG101) protein (UEV-TSG101) in mediating the release of genotype 3 HEV. Cyclic peptide (CP) inhibitors of the interaction between the human immunodeficiency virus (HIV) gag-PTAP motif and UEV-TSG101 are known to block the release of HIV. Using a molecular dynamic simulation, we observed that both gag-PTAP and ORF3-PSAP motifs bind to the same site in UEV-TSG101 by hydrogen bonding. HIV-released inhibitory CPs also displayed binding to the same site in UEV-TSG101, indicating that they may compete with ORF3-PSAP or gag-PTAP for binding to UEV-TSG101. Two independent assays confirmed the ability of a cyclic peptide (CP11) to inhibit the ORF3-TSG101 interaction. CP11 treatment also reduced the release of both genotype 1 and genotype 3 HEV by approximately 90%, with a 50% inhibitory concentration (IC50) of 2 μM. Thus, CP11 appears to be an attractive candidate for further validation of its anti-HEV properties.

IMPORTANCE There is no specific therapy against hepatitis E virus (HEV)-induced hepatic and nonhepatic health problems. Prevention of the release of the progeny viruses from infected cells is an attractive strategy to limit the spread of the virus. Interactions between the viral open reading frame 3 and the host tumor susceptibility gene 101 proteins have been shown to be essential for the release of genotype 3 HEV from infected cells. In this study, we have identified a cyclic peptide inhibitor of the above-mentioned interaction and demonstrate the efficiency of the inhibitor in preventing virus release from infected cells. Thus, our findings uncover the possibility of developing a specific antiviral agent against HEV by blocking its release from infected cells.

    Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

StephenW

病毒开放阅读框架3蛋白与宿主肿瘤易感基因101之间相互作用的环肽抑制剂有效抑制戊型肝炎病毒释放
Saumya Anang，Nidhi Kaushik，Smita Hingane，Anita Kumari，Jyoti Gupta，Shailendra Asthana，Shalimar，Baibaswata Nayak，C。T. Ranjith-Kumar，Milan Surjit
J.-H. James Ou，编辑
DOI：10.1128 / JVI.00684-18

    ArticleFigures＆DataInfo＆Metrics
    PDF

抽象

戊型肝炎病毒（HEV）通常在正常个体中引起自限性急性病毒性肝炎。它会导致免疫功能低下者和孕妇患上更严重的疾病。由于缺乏有效的细胞培养系统或动物模型，病毒的生命周期未得到充分研究，很少有抗病毒靶标已知，并且已经鉴定出很少有抗HEV感染的抗病毒候选物。抑制病毒释放是一种可能的抗病毒发展策略，它限制了病毒的传播。以前的研究已经证明了病毒开放阅读框3蛋白（ORF3-PSAP）的PSAP基序与宿主肿瘤易感基因101（TSG101）蛋白（UEV-TSG101）的UEV结构域之间相互作用的重要作用。释放基因型3 HEV。已知人免疫缺陷病毒（HIV）gag-PTAP基序和UEV-TSG101之间相互作用的环肽（CP）抑制剂阻断HIV的释放。使用分子动力学模拟，我们观察到gag-PTAP和ORF3-PSAP基序通过氢键结合到UEV-TSG101中的相同位点。 HIV释放的抑制性CP也显示出与UEV-TSG101中相同位点的结合，表明它们可能与ORF3-PSAP或gag-PTAP竞争结合UEV-TSG101。两个独立的测定证实了环肽（CP11）抑制ORF3-TSG101相互作用的能力。 CP11处理还使基因型1和基因型3 HEV的释放减少约90％，50％抑制浓度（IC50）为2μM。因此，CP11似乎是进一步验证其抗HEV特性的有吸引力的候选者。

重要性没有针对戊型肝炎病毒（HEV）引起的肝脏和非肝脏健康问题的特异性治疗。防止从感染细胞释放后代病毒是限制病毒传播的有吸引力的策略。已经显示病毒开放阅读框3和宿主肿瘤易感基因101蛋白之间的相互作用对于从感染细胞释放基因型3 HEV是必需的。在该研究中，我们鉴定了上述相互作用的环肽抑制剂，并证明了抑制剂在防止病毒从感染细胞中释放的效率。因此，我们的研究结果揭示了通过阻止其从感染细胞中释放来开发针对HEV的特异性抗病毒剂的可能性。

    版权所有©2018美国微生物学会。

版权所有。