Tolcapone Potently Inhibits Seminal Amyloid Fibrils Formation and Blocks Entry of Ebola Pseudoviruses
Tolcapone Potently Inhibits Seminal Amyloid Fibrils Formation and Blocks Entry of Ebola Pseudoviruses
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托卡朋有效抑制精液淀粉样原纤维的形成并阻止埃博拉假病毒的进入
DOI：
10.3389/fmicb.2020.00504
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发表时间：
2020
影响因子：
5.2
通讯作者：
Tan Suiyi
中科院分区：
文献类型：
--
作者：
Qiu Mengjie;Li Zhaofeng;Chen Yuliu;Guo Jiayin;Xu Wei;Qi Tao;Qiu Yurong;Pang Jianxin;Li Lin;Liu Shuwen;Tan Suiyi
埃博拉病毒（EBOV）是致命的EBOV病（EVD）的病原体，可以通过性传播。已发现精液淀粉样纤维是EBOV感染的增强剂。目前，有限的预防性疫苗或治疗可用于阻止EBOV通过性交感染。在这项研究中，我们重新利用托卡朋，美国食品和药物管理局（FDA）批准的帕金森氏病的代理，作为一种有效的抑制剂的精液淀粉样纤维，其中精液衍生的病毒感染增强剂（SEVI）是最好的特点。托卡朋与SEVI前体肽（PAP 248 -286）的淀粉样蛋白生成区域结合，并通过破坏PAP 248 -286寡聚化来抑制PAP 248 - 286聚集。此外，托卡朋与预先形成的SEVI原纤维相互作用，并影响SEVI在促进携带EBOV扎伊尔或苏丹种（分别为扎伊尔PsV和苏丹PsV）的包膜糖蛋白（GP）的假病毒（PsV）感染中的活性。托卡朋显着拮抗SEVI介导的增强扎伊尔PsV和苏丹PsV的结合，并随后在HeLa细胞的内化。值得注意的是，托卡朋也有效抑制扎伊尔PsV和苏丹PsV的进入。托卡朋可能通过与EBOV GP中的关键残基结合来抑制病毒进入。此外，托卡朋与两种小分子进入抑制剂（包括苄普地尔和舍曲林）的组合在精液中表现出协同的抗EBOV作用。总的来说，作为在性交期间靶向增强病毒感染的淀粉样蛋白和病毒本身的双功能药剂，托卡朋可以充当预防性局部药剂以防止EBOV的性传播或治疗EBOV感染的治疗剂。
Ebola virus (EBOV), the causative pathogen of the deadly EBOV disease (EVD), can be transmitted via sexual transmission. Seminal amyloid fibrils have been found enhancers of EBOV infection. Currently, limited preventive vaccine or therapeutic is available to block EBOV infection through sexual intercourse. In this study, we repurpose tolcapone, a US Food and Drug Administration (FDA)-approved agent for Parkinson’s disease, as a potent inhibitor of seminal amyloid fibrils, among which semen-derived enhancer of viral infection (SEVI) is the best-characterized. Tolcapone binds to the amyloidogenic region of the SEVI precursor peptide (PAP248–286) and inhibits PAP248–286 aggregation by disrupting PAP248–286 oligomerization. In addition, tolcapone interacts with preformed SEVI fibrils and influences the activity of SEVI in promoting infection of pseudovirus (PsV) carrying the envelope glycoprotein (GP) of the EBOV Zaire or Sudan species (Zaire PsV and Sudan PsV, respectively). Tolcapone significantly antagonizes SEVI-mediated enhancement of both Zaire PsV and Sudan PsV binding to and subsequent internalization in HeLa cells. Of note, tolcapone is also effective in inhibiting the entry of both Zaire PsV and Sudan PsV. Tolcapone inhibits viral entry possibly through binding with critical residues in EBOV GP. Moreover, the combination of tolcapone with two small-molecule entry inhibitors, including bepridil and sertraline, exhibited synergistic anti-EBOV effects in semen. Collectively, as a bifunctional agent targeting the viral infection-enhancing amyloid and the virus itself during sexual intercourse, tolcapone can act as either a prophylactic topical agent to prevent the sexual transmission of EBOV or a therapeutic to treat EBOV infection.