Structural basis of SARS-CoV-23CLpro and anti-COVID-19 drug discovery from medicinal plants / 药物分析学报

The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches / 药物分析学报

The papain-like protease (PLpro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro, which can be further developed as potential pan-PLpro based broad-spectrum antiviral drugs. The sequence, structure, and functional con-serveness of most deadly human CoVs PLpro were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease in-hibitors database composed of ～7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PLpro, and showed consistent interaction profile with SARS-CoV PLpro and MERS-CoV PLpro as well. Conclusively, the re-ported SARS-CoV-2 PLpro specific compounds could serve as seeds for developing potent pan-PLpro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented infor-mation related to binding site residual energy contribution could lead to further optimization of these compounds.

Comparison of Fentanyl and Remifentanil in children underwent airway foreign body removal / 中国内镜杂志

Objective To compare the safety and effectiveness of Propofol-Fentanyl and Propofol-Remifentanil total intravenous anesthesia for airway foreign body (FB) removal in children. Method 280 children aged 1 ~ 3 years underwent rigid bronchoscopy for FB removal were randomized into two groups. The Fentanyl group (Group F, n = 140) were given Propofol 2.00~3.00 mg/kg and Fentanyl 2.00 μg/kg for induction and Propofol 200.00 ~ 500.00 μg/(kg·min) for maintenance of anesthesia. The Remifentanil group (Group R, n = 140) were given Propofol 2.00 ~ 3.00 mg/kg and Remifentanil 1.00 ~ 1.50 μg/kg for induction of anesthesia, while anesthesia was maintained with Propofol 200.00 ~ 500.00 μg/(kg·min) and Remifentanil 0.10 ~ 0.20 μg/(kg·min). All the children during the procedure were with spontaneous respiration. SpO2 before inserting rigid bronchoscope (T1), 1 min (T2) and 3 min (T3) after insertion, 3 min (T4) and 10 min (T5) after extraction were recorded. PETCO2 after endoscopy (T6) was measured. Adverse events, including body movement, cough, breath-holding, and hypoxemia,were observed. The time of induction, surgery, recovery and the total dosage of the intravenous agents were recorded. Results SpO2 of the two groups were in normal range at T1 ~ 5, which was higher in group R than group F at T2 ~ 5 (P < 0.05). PETCO2 of group R was lower than group F at T6 (P < 0.05). The rate of body movement and cough were comparable between the two groups (P > 0.05), while breath-holding and hypoxemia were more frequent in group F (P < 0.05). The time of induction and recovery were shorter in group R (P < 0.05), while surgery time and the Propofol dosage were similar (P > 0.05). The total dose of Fentanyl was significantly higher than Remifentanil (P < 0.05). Conclusion Combination of Propofol with Fentanyl or Remifentanil both produce effective anesthesia in children undergoing FB removal. But Propofol-Remifentanil provides more stable oxygen saturation, faster induction and recurrence of anesthesia, as well as less intraoperative complications.