Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein.
Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein.
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DOI：
10.1021/acsnano.1c02057
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发表时间：
2021-08-24
期刊：
影响因子：
17.1
通讯作者：
Porotto M
中科院分区：
文献类型：
--
作者：
Bovier FT;Rybkina K;Biswas S;Harder O;Marcink TC;Niewiesk S;Moscona A;Alabi CA;Porotto M
尽管全球正在努力提高疫苗覆盖率，但麻疹病毒感染仍然是一个重大的公共卫生威胁。随着MeV根除工作的停滞和弱势群体的扩大，对MeV有效抗病毒药物的需求很大。在这里，我们描述了一种靶向MeV融合(F)蛋白的抗病毒肽的开发。这种抗病毒肽结构是由一个carbobenzoxy-d-Phe-l-Phe-Gly（融合抑制肽；FIP）偶联到一个脂化MeV F c末端七肽重复（HRC）结构域衍生物组成的。初步的体外测试显示出高抗病毒效力和特异性靶向MeV f相关细胞膜，具有最小的细胞毒性。FIP和hrc衍生的肽偶联物在单独给药时显示出协同抗病毒活性。然而，它们的化学偶联导致抗病毒效力显著增加。体外机制实验表明，FIP-HRC脂质偶联物主要通过稳定预灌注F发挥抗病毒活性，而hrc衍生肽则主要在激活后作用于F蛋白。结合体内实验显示，FIP-HRC脂质偶联物可有效预防棉花大鼠MeV感染，通过特异性靶向和稳定MeV预融合F结构，有望成为潜在的MeV抗病毒药物。
Measles virus (MeV) infection remains a significant public health threat despite ongoing global efforts to increase vaccine coverage. As eradication of MeV stalls, and vulnerable populations expand, effective antivirals against MeV are in high demand. Here, we describe the development of an antiviral peptide that targets the MeV fusion (F) protein. This antiviral peptide construct is composed of a carbobenzoxy-d-Phe-l-Phe-Gly (fusion inhibitor peptide; FIP) conjugated to a lipidated MeV F C-terminal heptad repeat (HRC) domain derivative. Initial in vitro testing showed high antiviral potency and specific targeting of MeV F-associated cell plasma membranes, with minimal cytotoxicity. The FIP and HRC-derived peptide conjugates showed synergistic antiviral activities when administered individually. However, their chemical conjugation resulted in markedly increased antiviral potency. In vitro mechanistic experiments revealed that the FIP–HRC lipid conjugate exerted its antiviral activity predominantly through stabilization of the prefusion F, while HRC-derived peptides alone act predominantly on the F protein after its activation. Coupled with in vivo experiments showing effective prevention of MeV infection in cotton rats, FIP–HRC lipid conjugates show promise as potential MeV antivirals via specific targeting and stabilization of the prefusion MeV F structure.
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影响因子：
4.6
作者：
Figueira TN;Freire JM;Cunha-Santos C;Heras M;Gonçalves J;Moscona A;Porotto M;Salomé Veiga A;Castanho MA
通讯作者：
Castanho MA
影响因子：
5.9
作者：
Griffin DE
通讯作者：
Griffin DE
DOI：
10.1126/science.aay6485
发表时间：
2019-11-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mina MJ;Kula T;Leng Y;Li M;de Vries RD;Knip M;Siljander H;Rewers M;Choy DF;Wilson MS;Larman HB;Nelson AN;Griffin DE;de Swart RL;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
158.5
作者：
DeVincenzo, John P.;Whitley, Richard J.;Chien, Jason W.
通讯作者：
Chien, Jason W.
麻疹病毒血凝素：对细胞进入的结构见解和麻疹疫苗。
影响因子：
5.2
作者：
Hashiguchi T;Maenaka K;Yanagi Y
通讯作者：
Yanagi Y