Chen Rui Hong, Yang Li Jun, Hamdoun Sami, Chung Sookja Kim, Lam Christopher Wai-Kei, Zhang Kai Xi, Guo Xiaoling, Xia Chenglai, Law Betty Yuen Kwan, Wong Vincent Kam Wai
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Department of Pharmaceutics, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan.
Front Pharmacol. 2021 Mar 4;12:634176. doi: 10.3389/fphar.2021.634176. eCollection 2021.
The outbreak of SARS-CoV-2 virus caused more than 80,155,187 confirmed COVID-19 cases worldwide, which has posed a serious threat to global public health and the economy. The development of vaccines and discovery of novel drugs for COVID-19 are urgently needed. Although the FDA-approved SARS-CoV-2 vaccines has been launched in many countries recently, the strength of safety, stringent storage condition and the possibly short-term immunized efficacy remain as the major challenges in the popularity and recognition of using vaccines against SARS-CoV-2. With the spike-receptor binding domain (RBD) of SARS-CoV-2 being responsible for binding to human angiotensin-converting enzyme 2 receptor (hACE2), ACE2 is identified as the receptor for the entry and viral infection of SARS-CoV-2. In this study, molecular docking and biolayer interferometry (BLI) binding assay were adopted to determine the direct molecular interactions between natural small-molecule, 1,2,3,4,6-Pentagalloyl glucose (PGG) and the spike-RBD of the SARS-CoV-2. Our results showed that PGG preferentially binds to a pocket that contains residues Glu 340 to Lys 356 of spike-RBD with a relatively low binding energy of -8 kcal/mol. BLI assay further confirmed that PGG exhibits a relatively strong binding affinity to SARS-CoV-2-RBD protein in comparison to hACE2. In addition, both ELISA and immunocytochemistry assay proved that PGG blocks SARS-CoV-2-RBD binding to hACE2 dose dependently in cellular level. Notably, PGG was confirmed to abolish the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of wild type SARS-CoV-2 virus in human host cells. Finally, maximal tolerated dose (MTD) studies revealed that up to 200 mg/kg/day of PGG was confirmed orally safe in mice. Our findings suggest that PGG may be a safe and potential antiviral agent against the COVID-19 by blockade the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors. Therefore, PGG may be considered as a safe and natural antiviral agent for its possible preventive application in daily anti-virus hygienic products such as a disinfectant spray or face mask.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒的爆发在全球范围内导致了超过80155187例确诊的新冠肺炎病例，这对全球公共卫生和经济构成了严重威胁。迫切需要研发针对新冠肺炎的疫苗和发现新型药物。尽管美国食品药品监督管理局（FDA）批准的SARS-CoV-2疫苗最近已在许多国家推出，但安全性、严格的储存条件以及可能的短期免疫效果等问题仍然是使用针对SARS-CoV-2疫苗的普及和认可度方面的主要挑战。由于SARS-CoV-2的刺突受体结合域（RBD）负责与人血管紧张素转换酶2受体（hACE2）结合，因此ACE2被确定为SARS-CoV-2进入和病毒感染的受体。在本研究中，采用分子对接和生物层干涉术（BLI）结合试验来确定天然小分子1,2,3,4,6-五没食子酰葡萄糖（PGG）与SARS-CoV-2的刺突-RBD之间的直接分子相互作用。我们的结果表明，PGG优先结合到一个包含刺突-RBD的谷氨酸340至赖氨酸356残基的口袋中，结合能相对较低，为-8千卡/摩尔。BLI试验进一步证实，与hACE2相比，PGG对SARS-CoV-2-RBD蛋白表现出相对较强的结合亲和力。此外，酶联免疫吸附测定（ELISA）和免疫细胞化学测定均证明，PGG在细胞水平上剂量依赖性地阻断SARS-CoV-2-RBD与hACE2的结合。值得注意的是，在过表达hACE2的HEK293细胞中，PGG被证实可消除RBD假型慢病毒的感染特性，这模拟了野生型SARS-CoV-2病毒进入人类宿主细胞的过程。最后，最大耐受剂量（MTD）研究表明，高达200毫克/千克/天的PGG经口服对小鼠是安全的。我们的研究结果表明，PGG可能是一种安全且有潜力的抗新冠肺炎病毒药物，通过阻断SARS-CoV-2刺突-RBD与hACE2受体的融合来发挥作用。因此，鉴于PGG可能在日常抗病毒卫生产品如消毒喷雾或口罩中的预防性应用，它可被视为一种安全的天然抗病毒剂。
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