Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai, China.
Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, China.
mBio. 2024 May 8;15(5):e0074124. doi: 10.1128/mbio.00741-24. Epub 2024 Apr 9.
Outbreaks of acute respiratory viral diseases, such as influenza and COVID-19 caused by influenza A virus (IAV) and SARS-CoV-2, pose a serious threat to global public health, economic security, and social stability. This calls for the development of broad-spectrum antivirals to prevent or treat infection or co-infection of IAV and SARS-CoV-2. Hemagglutinin (HA) on IAV and spike (S) protein on SARS-CoV-2, which contain various types of glycans, play crucial roles in mediating viral entry into host cells. Therefore, they are key targets for the development of carbohydrate-binding protein-based antivirals. This study demonstrated that griffithsin (GRFT) and the GRFT-based bivalent entry inhibitor GL25E (GRFT-L25-EK1) showed broad-spectrum antiviral effects against IAV infection by binding to HA in a carbohydrate-dependent manner and effectively protected mice from lethal IAV infection. Although both GRFT and GL25E could inhibit infection of SARS-CoV-2 Omicron variants, GL25E proved to be significantly more effective than GRFT and EK1 alone. Furthermore, GL25E effectively inhibited co-infection of IAV and SARS-CoV-2 and demonstrated good druggability, including favorable safety and stability profiles. These findings suggest that GL25E is a promising candidate for further development as a broad-spectrum antiviral drug for the prevention and treatment of infection or co-infection from IAV and SARS-CoV-2.IMPORTANCEInfluenza and COVID-19 are highly contagious respiratory illnesses caused by the influenza A virus (IAV) and SARS-CoV-2, respectively. IAV and SARS-CoV-2 co-infection exacerbates damage to lung tissue and leads to more severe clinical symptoms, thus calling for the development of broad-spectrum antivirals for combating IAV and SARS-CoV-2 infection or co-infection. Here we found that griffithsin (GRFT), a carbohydrate-binding protein, and GL25E, a recombinant protein consisting of GRFT, a 25 amino acid linker, and EK1, a broad-spectrum coronavirus inhibitor, could effectively inhibit IAV and SARS-CoV-2 infection and co-infection by targeting glycans on HA of IAV and spike (S) protein of SARS-CoV-2. GL25E is more effective than GRFT because GL25E can also interact with the HR1 domain in SARS-CoV-2 S protein. Furthermore, GL25E possesses favorable safety and stability profiles, suggesting that it is a promising candidate for development as a drug to prevent and treat IAV and SARS-CoV-2 infection or co-infection.
急性呼吸道病毒病（如流感和由甲型流感病毒（IAV）和 SARS-CoV-2 引起的 COVID-19）的爆发对全球公共卫生、经济安全和社会稳定构成了严重威胁。这就需要开发广谱抗病毒药物来预防或治疗 IAV 和 SARS-CoV-2 的感染或合并感染。IAV 上的血凝素（HA）和 SARS-CoV-2 上的刺突（S）蛋白都含有多种类型的聚糖，在介导病毒进入宿主细胞方面发挥着关键作用。因此，它们是基于碳水化合物结合蛋白的抗病毒药物开发的关键靶标。本研究表明，griffithsin（GRFT）和基于 GRFT 的双价进入抑制剂 GL25E（GRFT-L25-EK1）通过与 HA 结合以碳水化合物依赖的方式对 IAV 感染具有广谱抗病毒作用，并有效保护小鼠免受致命的 IAV 感染。虽然 GRFT 和 GL25E 都可以抑制 SARS-CoV-2 奥密克戎变体的感染，但 GL25E 比 GRFT 和 EK1 单独使用时更有效。此外，GL25E 有效抑制了 IAV 和 SARS-CoV-2 的合并感染，并且具有良好的成药性，包括有利的安全性和稳定性特征。这些发现表明，GL25E 是一种很有前途的候选药物，可进一步开发为预防和治疗 IAV 和 SARS-CoV-2 感染或合并感染的广谱抗病毒药物。
重要性：流感和 COVID-19 分别是由甲型流感病毒（IAV）和 SARS-CoV-2 引起的高度传染性呼吸道疾病。IAV 和 SARS-CoV-2 的合并感染会加重肺组织损伤，并导致更严重的临床症状，因此需要开发广谱抗病毒药物来对抗 IAV 和 SARS-CoV-2 的感染或合并感染。在这里，我们发现碳水化合物结合蛋白 griffithsin（GRFT）和由 GRFT、25 个氨基酸接头和广谱冠状病毒抑制剂 EK1 组成的重组蛋白 GL25E 可以通过靶向 IAV 的 HA 和 SARS-CoV-2 的刺突（S）蛋白上的聚糖来有效抑制 IAV 和 SARS-CoV-2 的感染和合并感染。GL25E 比 GRFT 更有效，因为 GL25E 还可以与 SARS-CoV-2 S 蛋白的 HR1 结构域相互作用。此外，GL25E 具有良好的安全性和稳定性特征，表明它是一种很有前途的候选药物，可开发用于预防和治疗 IAV 和 SARS-CoV-2 的感染或合并感染。
Arch Virol. 2012-10-7
Antimicrob Agents Chemother. 2015-12
Antiviral Res. 2016-9
Trends Immunol. 2024-2
Emerg Microbes Infect. 2023-12
Zotero 插件
