Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure and Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua Universitygrid.12527.33, Beijing, China.
Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
mBio. 2022 Aug 30;13(4):e0148522. doi: 10.1128/mbio.01485-22. Epub 2022 Jul 13.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19). Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all- retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. Retinoids, a group of compounds including vitamin A and its active metabolite all- retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致全球大流行和危及生命的 2019 年冠状病毒病（COVID-19）的病原体。尽管有疫苗和治疗性抗体可用，但它们的功效不断受到 SARS-CoV-2 迅速出现的变体的削弱。在这里，我们发现全反式维甲酸（ATRA），一种维生素 A（视黄醇）衍生物，在人细胞系和人下呼吸道类器官中对所有 SARS-CoV-2 变体均表现出强大的抗病毒活性。从机制上讲，ATRA 直接结合在 SARS-CoV-2 刺突蛋白（S）三聚体顶部的受体结合域（RBD）的一个深疏水性口袋中。结合的 ATRA 介导“向下”RBD 之间的强相互作用，并将大多数 S 三聚体锁定在 RBD“全向下”和 ACE2 不可接近的抑制构象中。总之，我们的研究结果揭示了 ATRA 和其他维甲酸类化合物在 SARS-CoV-2 感染中的药理作用靶点和结构机制，并表明 ATRA 及其衍生物可能是针对广泛冠状病毒的潜在有效化合物。
维甲酸类化合物是一组包括维生素 A 和其活性代谢产物全反式维甲酸（ATRA）的化合物，调节多个器官系统中的一系列生理活性，如细胞生长、分化和凋亡。迄今为止报道的 ATRA 类似物包括 4000 多种天然和合成分子，这些分子在结构和/或功能上与 ATRA 相关。在这里，我们发现 ATRA 通过直接结合在 SARS-CoV-2 刺突蛋白（S）三聚体顶部的受体结合域（RBD）中的一个深疏水性口袋，对所有 SARS-CoV-2 变体均表现出强大的抗病毒活性。结合的 ATRA 介导“向下”RBD 之间的强相互作用，并将大多数 S 三聚体锁定在 RBD“全向下”和 ACE2 不可接近的抑制构象中，这表明使用 ATRA 或其衍生物作为 COVID-19 疾病治疗和预防的药理学可行性。
