A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants.

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Discovery of 3-phenyl-1,2,4-oxadiazole derivatives as a new class of SARS-CoV-2 main protease inhibitors.

The ongoing COVID-19 pandemic has led to massive infections and deaths and caused tremendous grief among the people. Although vaccines have played an important role in fighting COVID-19, the situation that the protective effect of current vaccines significantly decreases against mutated strains reminds us of the pressing need for developing effective antiviral therapeutics. The main protease (Mpro) is a key enzyme for SARS-CoV-2 viral replication and transcription and an attractive target for drug development. In this research, we report a new series of Mpro inhibitors containing 3-phenyl-1,2,4-oxadiazole. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, 16d, which showed an IC50 value of 5.27 ± 0.26 µM. Collectively, we obtained a new small molecular inhibitor targeting SARS-CoV-2 Mpro, which contains a new scaffold. This compound could be taken as a lead compound for subsequent drug discovery against SARS-CoV-2.

Prediction of Pulmonary Function Parameters Based on a Combination Algorithm.

OBJECTIVE: Pulmonary function parameters play a pivotal role in the assessment of respiratory diseases. However, the accuracy of the existing methods for the prediction of pulmonary function parameters is low. This study proposes a combination algorithm to improve the accuracy of pulmonary function parameter prediction. METHODS: We first established a system to collect volumetric capnography and then processed the data with a combination algorithm to predict pulmonary function parameters. The algorithm consists of three main parts: a medical feature regression structure consisting of support vector machines (SVM) and extreme gradient boosting (XGBoost) algorithms, a sequence feature regression structure consisting of one-dimensional convolutional neural network (1D-CNN), and an error correction structure using improved K-nearest neighbor (KNN) algorithm. RESULTS: The root mean square error (RMSE) of the pulmonary function parameters predicted by the combination algorithm was less than 0.39L and the R2 was found to be greater than 0.85 through a ten-fold cross-validation experiment. CONCLUSION: Compared with the existing methods for predicting pulmonary function parameters, the present algorithm can achieve a higher accuracy rate. At the same time, this algorithm uses specific processing structures for different features, and the interpretability of the algorithm is ensured while mining the feature depth information.

Impact of the COVID-19 Pandemic on ST-Elevation Myocardial Infarction Management in Hunan Province, China: A Multi-Center Observational Study.

Background: This study aimed to investigate the impact of the COVID-19 pandemic on ST-segment elevation myocardial infarction (STEMI) care in China. Methods: We conducted a multicenter, retrospective cohort study in Hunan province (adjacent to the epidemic center), China. Consecutive patients presenting with STEMI within 12 h of symptom onset and receiving primary percutaneous coronary intervention, pharmaco-invasive strategy and only thrombolytic treatment, were enrolled from January 23, 2020 to April 8, 2020 (COVID-19 era group). The same data were also collected for the equivalent period of 2019 (pre-COVID-19 era group). Results: A total of 610 patients with STEMI (COVID-19 era group n = 286, pre-COVID-19 era group n = 324) were included. There was a decline in the number of STEMI admissions by 10.5% and STEMI-related PCI procedures by 12.7% in 2020 compared with the equivalent period of 2019. The key time intervals including time from symptom onset to first medical contact, symptom onset to door, door-to-balloon, symptom onset to balloon and symptom onset to thrombolysis showed no significant difference between these two groups. There were no significant differences for in-hospital death and major adverse cardiovascular events between these two groups. Conclusion: During the COVID-19 pandemic outbreak in China, we observed a decline in the number of STEMI admissions and STEMI-related PCI procedures. However, the key quality indicators of STEMI care were not significantly affected. Restructuring health services during the COVID-19 pandemic has not significantly adversely influenced the in-hospital outcomes.