Evaluation of the Inhibition Potency of Nirmatrelvir against Main Protease Mutants of SARS-CoV-2 Variants.

SARS-CoV-2 continues to pose a threat to public health. Main protease (Mpro) is one of the most lucrative drug targets for developing specific antivirals against SARS-CoV-2 infection. By targeting Mpro, peptidomimetic nirmatrelvir is able to inhibit viral replication of SARS-CoV-2 and reduce the risk for progression to severe COVID-19. However, multiple mutations in the gene encoding Mpro of emerging SARS-CoV-2 variants raise a concern of drug resistance. In the present study, we expressed 16 previously reported SARS-CoV-2 Mpro mutants (G15S, T25I, T45I, S46F, S46P, D48N, M49I, L50F, L89F, K90R, P132H, N142S, V186F, R188K, T190I, and A191V). We evaluated the inhibition potency of nirmatrelvir against these Mpro mutants and solved the crystal structures of representative Mpro mutants of SARS-CoV-2 bound to nirmatrelvir. Enzymatic inhibition assays revealed that these Mpro variants remain susceptible to nirmatrelvir as the wildtype. Detailed analysis and structural comparison provided the inhibition mechanism of Mpro mutants by nirmatrelvir. These results informed the ongoing genomic surveillance of drug resistance of emerging SARS-CoV-2 variants to nirmatrelvir and facilitate the development of next-generation anticoronavirus drugs.

Structural Basis for the Inhibition of Coronaviral Main Proteases by a Benzothiazole-Based Inhibitor.

The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Mpros. Crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Mpros from other coronaviruses. In consideration of the important role of Mpro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral Mpro inhibitors that are safer and more effective.

Do Coastal Areas Experience More Recession during the Economic Crisis-Evidence from China.

The notion of resilience has been increasingly adopted in economic geography, concerning how regions resist and recover from all kinds of shocks. Most of the literature on the resilience of coastal areas focuses on biophysical stressors, such as climate change and some environmental factors. In this research, we analyze the regional economic resilience characteristics responding to the Great Financial Crisis in 2008 and its main determinants. We conclude that the coastal areas encountered more recession (or less growth) in the long term, and the secondary industry showed higher resilience than the tertiary industry. The influential factors of regional economic resilience varied across different stages of the crisis, and for the long term, good financial arrangement and governance ability could prompt the regional resilience to the crisis. Finally, some policy implications are proposed which may benefit dealings with major shocks such as economic crises and COVID-19.

Structure-Based Discovery and Structural Basis of a Novel Broad-Spectrum Natural Product against the Main Protease of Coronavirus.

Over the past 20 years, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2 emerged, causing severe human respiratory diseases throughout the globe. Developing broad-spectrum drugs would be invaluable in responding to new, emerging coronaviruses and to address unmet urgent clinical needs. Main protease (Mpro; also known as 3CLpro) has a major role in the coronavirus life cycle and is one of the most important targets for anti-coronavirus agents. We show that a natural product, noncovalent inhibitor, shikonin, is a pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, human coronavirus (HCoV)-HKU1, HCoV-NL63, and HCoV-229E with micromolar half maximal inhibitory concentration (IC50) values. Structures of the main protease of different coronavirus genus, SARS-CoV from the betacoronavirus genus and HCoV-NL63 from the alphacoronavirus genus, were determined by X-ray crystallography and revealed that the inhibitor interacts with key active site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses as well as emerging coronaviruses of the future. Given the importance of the main protease for coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. IMPORTANCE The current pandemic has created an urgent need for broad-spectrum inhibitors of SARS-CoV-2. The main protease is relatively conservative compared to the spike protein and, thus, is one of the most promising targets in developing anti-coronavirus agents. We solved the crystal structures of the main protease of SARS-CoV and HCoV-NL63 that bound to shikonin. The structures provide important insights, have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad-spectrum anti-coronavirus ligands as new therapeutic agents.

Crystal structures of human coronavirus NL63 main protease at different pH values.

Human coronavirus NL63 (HCoV-NL63), which belongs to the genus Alphacoronavirus, mainly infects children and the immunocompromized and is responsible for a series of clinical manifestations, including cough, fever, rhinorrhoea, bronchiolitis and croup. HCoV-NL63, which was first isolated from a seven-month-old child in 2004, has led to infections worldwide and accounts for 10% of all respiratory illnesses caused by etiological agents. However, effective antivirals against HCoV-NL63 infection are currently unavailable. The HCoV-NL63 main protease (Mpro), also called 3C-like protease (3CLpro), plays a vital role in mediating viral replication and transcription by catalyzing the cleavage of replicase polyproteins (pp1a and pp1ab) into functional subunits. Moreover, Mpro is highly conserved among all coronaviruses, thus making it a prominent drug target for antiviral therapy. Here, four crystal structures of HCoV-NL63 Mpro in the apo form at different pH values are reported at resolutions of up to 1.78 Å. Comparison with Mpro from other human betacoronaviruses such as SARS-CoV-2 and SARS-CoV reveals common and distinct structural features in different genera and extends knowledge of the diversity, function and evolution of coronaviruses.

What matters for regional economic resilience amid COVID-19? Evidence from cities in Northeast China.

This paper examines how the economies of old industrial cities in Northeast China respond to the on-going COVID-19 pandemic crisis. The notion of resistance in regional economic resilience is used to explore what impact factors shape the response to the early stage of the crisis. The analysis reveals significant differences in terms of regional economic impact between COVID-19 and the 2008 financial crisis. We find that large cities are more vulnerable and exposed to the pandemic at its early stage, state agency plays a crucial role in shaping the economic resistance in most cities. Going beyond the existing 2008 financial crisis-induced account on regional economic resilience, this paper argues that regional resistance amid COVID-19 is not merely shaped by economic structural factors but also influenced by state agency in terms of economic restriction and restoration measures. The study suggests that the nature of COVID-19 as a particular context of crisis itself needs to be taken seriously when exploring the determinants and outcomes of regional economic resilience.

Depressive, anxiety, and insomnia symptoms between population in quarantine and general population during the COVID-19 pandemic: a case-controlled study.

BACKGROUND: The COVID-19 pandemic have caused mental and psychological problems on the general population, patients, and related workers. Our study is to determine the impact of mental and psychological symptoms among population in quarantine for 2 weeks during COVID-19 pandemic. METHODS: A case-controlled study design have conducted at department of psychiatry of Shenzhen Longgang Center for Chronic Disease Control in Shenzhen, China mainland from 7th April to 15th June 2020.1674 participants (aged 18 to 65 years) in quarantine for 2 weeks and 1743 age-sex matched controls living in Shenzhen were recruited between 7th April 2020 and 15th June 2020. The assessment of depressive, anxiety, and insomnia symptoms were determined by self-reported questionnaires PHQ-9, GAD-7, and ISI, respectively. RESULTS: A total of 1674 participants in quarantine for 2 weeks and 1743 age-sex matched controls (32.6 ± 9.3 years vs. 32.7 ± 10.7 years, 49.8% vs. 47.8% females) were recruited. Population in quarantine had higher score on PHQ-9 (6.1 ± 5.5 vs. 3.0 ± 3.7, p < 0.001), GAD-7 (4.2 ± 4.7 vs. 1.9 ± 3.7, p < 0·001), and ISI (5.5 ± 5.8 vs. 3.1 ± 5.0%, p < 0.001) compared to general population. Population in quarantine showed significantly higher risks of depression (OR: 4.55, 95% CI: 3.82-5.41), anxiety (OR: 2.92, 95% CI: 2.43-3.51), and insomnia (OR: 2.40, 95% CI: 2.02-2.89), when compared to the general population. Younger, more education, non-married and lower household income showed higher risks of mental health problems. CONCLUSIONS: Population in quarantine had a higher level of depressive, anxiety, and insomnia symptoms than controls. Specifically, they were at a higher risk prevalence of depression, anxiety, and insomnia, especially the severity of depression, when compared to controls. Younger, more education, non-married, and lower income population in quarantine were at higher risks of mental health problems. Mental health professionals should pay attention to the mental and psychological symptoms for population in quarantine.