基于肽的膜融合抑制剂靶向 HCoV-229E 刺突蛋白 HR1 和 HR2 结构域。

Peptide-Based Membrane Fusion Inhibitors Targeting HCoV-229E Spike Protein HR1 and HR2 Domains.

机构信息

Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, 130 Dong An Rd., Xuhui District, Shanghai 200032, China.

Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, The Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Fudan University, Shanghai 200032, China.

出版信息

Int J Mol Sci. 2018 Feb 6;19(2):487. doi: 10.3390/ijms19020487.

Human coronavirus 229E (HCoV-229E) infection in infants, elderly people, and immunocompromised patients can cause severe disease, thus calling for the development of effective and safe therapeutics to treat it. Here we reported the design, synthesis and characterization of two peptide-based membrane fusion inhibitors targeting HCoV-229E spike protein heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, 229E-HR1P and 229E-HR2P, respectively. We found that 229E-HR1P and 229E-HR2P could interact to form a stable six-helix bundle and inhibit HCoV-229E spike protein-mediated cell-cell fusion with IC of 5.7 and 0.3 µM, respectively. 229E-HR2P effectively inhibited pseudotyped and live HCoV-229E infection with IC of 0.5 and 1.7 µM, respectively. In a mouse model, 229E-HR2P administered intranasally could widely distribute in the upper and lower respiratory tracts and maintain its fusion-inhibitory activity. Therefore, 229E-HR2P is a promising candidate for further development as an antiviral agent for the treatment and prevention of HCoV-229E infection.

人冠状病毒 229E（HCoV-229E）感染婴幼儿、老年人和免疫功能低下的患者可导致严重疾病，因此需要开发有效和安全的治疗方法。在这里，我们报告了两种针对 HCoV-229E 刺突蛋白七肽重复 1（HR1）和七肽重复 2（HR2）结构域的基于肽的膜融合抑制剂的设计、合成和表征，分别为 229E-HR1P 和 229E-HR2P。我们发现 229E-HR1P 和 229E-HR2P 可以相互作用形成稳定的六螺旋束，并分别以 5.7 和 0.3 µM 的 IC 抑制 HCoV-229E 刺突蛋白介导的细胞-细胞融合。229E-HR2P 可有效抑制假型和活的 HCoV-229E 感染，IC 分别为 0.5 和 1.7 µM。在小鼠模型中，鼻内给予 229E-HR2P 可广泛分布在上呼吸道和下呼吸道，并保持其融合抑制活性。因此，229E-HR2P 是进一步开发作为治疗和预防 HCoV-229E 感染的抗病毒药物的有前途的候选药物。