Discovery of novel inhibitors of SARS-CoV-2 main protease.

Corona Virus Disease 2019 (COVID-19), referred to as 'New Coronary Pneumonia', is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 µM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs.Communicated by Ramaswamy H. Sarma.

[Analysis of the changes of inflammatory cytokine levels in patients with critical coronavirus disease 2019 undergoing invasive mechanical ventilation].

OBJECTIVE: To investigate the relationship between the changes of inflammatory cytokine levels and prognosis of patients with critical coronavirus disease 2019 (COVID-19) undergoing invasive mechanical ventilation (IMV). METHODS: A retrospective study was conducted. The clinical date of critical COVID-19 patients undergoing IMV who were hospitalized in Wuhan Union Hospital, Tongji Medical College of Huazhong University of Science and Technology from February 4th to March 25th in 2020 were collected. At the same time, the inflammatory cytokine levels including interleukins (IL-2, IL-4, IL-6, IL-10) and tumor necrosis factor-α (TNF-α) at 48 hours before IMV and 48 hours after IMV of all the patients, as well as the 48 hours after weaning or right before death were recorded. Multivariate unconditional Logistic regression analysis was used to screen the independent risk factors of death during hospitalization. RESULTS: Among the 43 patients, 13 patients improved and 30 died. Compared with the survival group, the patients in the non-survival group were older (years old: 67.6±7.3 vs. 58.5±11.9, P < 0.05), with higher rates of hypertension, diabetes and coronary heart disease (53.3% vs. 15.4%, 63.3% vs. 23.1%, 26.7% vs. 0%, all P < 0.05), and the time from onset to admission to hospital, admission to ICU and IMV were longer (days: it was 9.17±5.00 vs. 5.07±2.49, 17.10±7.11 vs. 12.23±5.05, and 17.90±7.46 vs. 12.61±5.60, respectively, all P < 0.05). The IL-6 and TNF-α levels on 48 hours after IMV in the non-survival patients increased significantly as compared with those before 48 hours and the surviving patients. Especially, the IL-6 levels increased significantly as compared with those at 48 hours after IMV and 48 hours after weaning in the surviving patients [ng/L: 800.00 (194.25, 2 000.00) vs. 22.03 (6.66, 28.21), 3 204.00 (1 264.88, 5 000.00) vs. 5.00 (3.98, 12.27), both P < 0.01]. The IL-10 level before death in the non-survival patients increased significantly as compared with that at 48 hours after weaning in the surviving patients [ng/L: 55.89 (26.07, 100.14) vs. 3.53 (2.76, 12.36), P < 0.05]. There were no significant differences in the levels of IL-2 and IL-4 between the two groups at every time point. The variables of age, basic diseases, the IL-6 level after IMV were included in the multivariate unconditional Logistic regression analysis, which showed that age [odds ratio (OR) = 0.821, 95% confidence interval (95%CI) was 0.695-0.968], hypertension (OR = 0.027, 95%CI was 0.002-0.378), diabetes mellitus (OR = 0.054, 95%CI was 0.005-0.611), coronary heart disease (OR = 0.042, 95%CI was 0.002-0.968) and the IL-6 level after IMV (OR = 0.902, 95%CI was 0.819-0.994) were independent risk factors for death during hospitalization in patients with critical COVID-19 undergoing IMV (all P < 0.05). CONCLUSIONS: The levels of inflammatory cytokine including IL-6, IL-10, and TNF-α increased significantly with aggravation in critical COVID-19 patients undergoing IMV, especially IL-6. IL-6 was an independent risk factor for death of critical COVID-19 patients undergoing IMV.

The associated factors of cesarean section during COVID-19 pandemic: a cross-sectional study in nine cities of China.

BACKGROUND: Improving and maintaining the health of mothers and newborns is indisputably a global priority, especially during a pandemic. This study intends to examine the factors associated with cesarean section (CS) during lockdown time. METHODS: A total of 678 women who just gave birth within 7 days were enrolled from maternal and children hospitals in nine cities of China from April to May 2020. The delivery modes and potential influencing factors were investigated. The subgroup analysis and sensitivity analysis were used to examine the association of CS and risk factors among populations with different characteristics and to control for possible confounding, respectively. RESULTS: The overall rate of cesarean delivery was 37.3%. In multi-variant model, maternal age > 30 years (OR, 95% CI = 1.71, 1.21-2.41), higher pre-gestational BMI (OR, 95% CI = 1.16, 1.10-1.23), living in regions with confirmed COVID-19 cases > 500 (OR, 95% CI = 2.45, 1.74-3.45), and excess gestational weight gain (OR, 95% CI = 1.73, 1.17-2.55) were associated with cesarean delivery. These trends of associations were not changes in sensitivity analysis and subgroup analysis. Cesarean delivery occurred more in women who got more nutrition instruction during the pandemic period in the univariant model; however, this association showed insignificance in the multiple-variant analysis. CONCLUSION: A high cesarean delivery rate was found in uninfected women who experienced lockdown in their third trimester. During the COVID-19 pandemic, more medical support should be provided in severely affected regions to ensure and promote health in pregnancy.