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.

Measuring farmers' sustainable livelihood resilience in the context of poverty alleviation: a case study from Fugong County, China.

In recent years, the sustainable livelihood of farmers has been threatened by various events such as the COVID-19 pandemic, which has significantly impacted efforts to alleviate poverty. Therefore, it is vitally important to increase farmers' sustainable livelihood resilience to enhance the stability and sustainability of poverty alleviation efforts. In this study, to scientifically measure and analyze farmers' sustainable livelihood resilience, we designed an analytical framework that captures the characteristics of farmers' sustainable livelihood resilience from the three dimensions of buffer capacity, self-organization capacity, and learning capacity. We then constructed an index system of farmers' sustainable livelihood resilience and a cloud-model-based multi-level fuzzy comprehensive evaluation model. Finally, the coupling coordination degree and decision tree methods were used to identify the level of development and relationships among the three abovementioned dimensions of farmers' sustainable livelihood resilience. A case study from Fugong County, Yunnan Province, China revealed that the spatial and temporal distributions of farmers' sustainable livelihood resilience were heterogeneous across various regions. Furthermore, the spatial distribution of the coordinated development level of farmers' sustainable livelihood resilience is similar to that of its overall level because the three dimensions of buffer capacity, self-organization capacity, and learning capacity interact with each other and develop synergistically, and the lack of any one of these affects the overall development of farmers' sustainable livelihood resilience. In addition, the sustainable livelihood resilience of farmers in various villages is in a state of stable promotion, benign promotion, stagnation, mild recession, severe recession, or chaotic period, indicating a lack of balance in terms of the state of development. However, sustainable livelihood resilience will gradually improve in response to targeted support policies formulated by the national or local governments.

Investor attention and the COVID-19 concept stocks in China's stock market

Purpose This paper investigates the impact of investor attention on the COVID-19 concept stocks in China's stock market from the perspectives of the macroeconomy, the stock market and the COVID-19 pandemic. Design/methodology/approach On the basis of controlling the time effects and individual fixed effects, this paper studies the impact of investor attention on the COVID-19 concept stocks in China's stock market through a set of fixed effect panel data models. Among them, investor attention focuses on macroeconomy, stock market and the COVID-19 pandemic, respectively, while stock indicators cover return, volatility and turnover. In addition, this paper also examines the heterogeneity influence of investor attention on the COVID-19 concept stocks from the perspective of time and stock classification. Findings Findings indicate that the attention to macroeconomy does not have a statistically significant effect on the return, unlike the attention to stock market and COVID-19 incident. Three types of investor attention have significant positive effects on the volatility and turnover rate. During the outbreak of the domestic epidemic, the impact of investor attention was significantly higher than that during the outbreak of the epidemic overseas. A finer-grained analysis shows that the attention to stock market has significantly increased the return of preventive type and treatment type stocks, while diagnostic-related stocks have been most affected by the attention to COVID-19 incident. Research limitations/implications The major limitation of this work is the construction of investor attention. Although Baidu index is widely used, investor attention can be assessed more accurately based on more unstructured data. In addition, the effect of the COVID-19 can also be investigated in a longer time domain. Further research can be combined with the dynamics of the COVID-19 pandemic to more comprehensively evaluate its impact on the stock market. Originality/value The research proves that investor attention plays an important role in stock pricing and provides empirical evidence on the behavioral foundations of the conceptual sector of the stock market under uncertainty. It also has practical implications for regulators and investors interested in conducting accurate asset allocation and risk assessment.

An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Clinical differences in chest CT characteristics between the progression and remission stages of patients with COVID-19 pneumonia.

INTRODUCTION: Computed tomography (CT) can be effective for the early screening and diagnosis of COVID-19. This study aimed to investigate the distinctive CT characteristics of two stages of the disease (progression and remission). METHODS: We included all COVID-19 patients admitted to Wenzhou Central Hospital from January to February, 2020. Patients underwent multiple chest CT scans at intervals of 3-10 days. CT features were recorded, such as the lesion lobe, distribution characteristics (subpleural, scattered or diffused), shape of the lesion, maximum size of the lesion, lesion morphology (ground-glass opacity, GGO) and consolidation features. When consolidation was positive, the boundary was identified to determine its clarity. RESULTS: The ratios of some representative features differed between the remission stage and the progression phase, such as round-shape lesion (8.0% vs 34.4%), GGO (65.0% vs 87.5%), consolidation (62.0% vs 31.3%), large cable sign (59.0% vs 9.4%) and crazy-paving sign (20.0% vs 50.0%). Using these features, we pooled all the CT data (n = 132) and established a logistic regression model to predict the current development stage. The variables consolidation, boundary feature, large cable sign and crazy-paving sign were the most significant factors, based on a variable named "prediction of progression or remission" (PPR) that we constructed. The ROC curve showed that PPR had an AUC of 0.882 (cutoff value = 0.66, sensitivity = 0.75, specificity = 0.875). CONCLUSION: CT characteristics, in particular, round shape, GGO, consolidation, large cable sign, and crazy-paving sign, may increase the recognition of the intrapulmonary development of COVID-19.