State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Antiviral Res. 2022 Dec;208:105450. doi: 10.1016/j.antiviral.2022.105450. Epub 2022 Oct 29.
FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC = 0.39 ± 0.01 μM, EC = 0.75 ± 0.01 μM; B.1.351 (Beta): EC = 0.28 ± 0.11 μM, EC = 0.57 ± 0.21 μM; B.1.617.2 (Delta): EC = 0.27 ± 0.05 μM, EC = 0.81 ± 0.20 μM; B.1.1.529 (Omicron): EC = 0.26 ± 0.06 μM and EC = 0.042 ± 0.007 μM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed C in plasma and predicted C of lung total concentration were 0.163 and 2.5 μg/mL, which were approximately 9 and 132-fold higher than the EC of 0.019 μg/mL (0.042 μM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934).
FB2001 是一种针对 SARS-CoV-2 主要蛋白酶的候选药物，通过与半胱氨酸 145 共价结合。在这项研究中，我们评估了 FB2001 在体外和体内（在小鼠中）对几种 SARS-CoV-2 变体的抑制活性，我们还评估了 FB2001 对肺部和大脑的组织病理学分析和免疫染色，这在以前的研究中很少报道。结果表明，FB2001 对 Vero E6 细胞中的几种当前 SARS-CoV-2 变体表现出强大的抗病毒功效，即 B.1.1.7（Alpha）：EC=0.39±0.01 μM，EC=0.75±0.01 μM；B.1.351（Beta）：EC=0.28±0.11 μM，EC=0.57±0.21 μM；B.1.617.2（Delta）：EC=0.27±0.05 μM，EC=0.81±0.20 μM；B.1.1.529（Omicron）：EC=0.26±0.06 μM 和 EC=0.042±0.007 μM（在 P-糖蛋白抑制剂存在的情况下）。FB2001 在存在高浓度人血清的情况下仍然对 SARS-CoV-2 复制具有强大的抑制作用，这表明人血清对体外抑制活性没有显著影响。此外，当与瑞德西韦联合使用时，该抑制剂对 SARS-CoV-2 表现出相加作用。此外，FB2001 可显著降低体内肺部和大脑中的 SARS-CoV-2 拷贝数和滴度，并减轻病理症状。此外，FB2001 可减轻脑组织中局部出血、红细胞溢出、水肿和炎症细胞浸润，并且抑制病毒滴度和改善大脑炎症的抑制剂很少有报道。建立并验证了基于生理学的药代动力学模型以预测 FB2001 在人体肺部中的浓度。当 FB2001 以 200mg 每天两次给药 5 天时，观察到的血浆 C 和预测的肺总浓度 C 分别为 0.163 和 2.5μg/mL，这大约是对 Omicron 变体的 0.019μg/mL（0.042μM）的 EC 的 9 和 132 倍。总之，我们的研究表明，FB2001 是 COVID-19 治疗的一种有前途的治疗药物，可与瑞德西韦联合使用以实现改善的临床结果。由于其在健康人类中的良好安全性和耐受性（NCT05197179 和 NCT04766931），FB2001 已被批准用于 II/III 期临床试验（NCT05445934）。
