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.

Quantifying the impacts of human mobility restriction on the spread of coronavirus disease 2019: an empirical analysis from 344 cities of China.

BACKGROUND: Since the outbreak of coronavirus disease 2019 (COVID-19), human mobility restriction measures have raised controversies, partly because of the inconsistent findings. An empirical study is promptly needed to reliably assess the causal effects of the mobility restriction. The purpose of this study was to quantify the causal effects of human mobility restriction on the spread of COVID-19. METHODS: Our study applied the difference-in-difference (DID) model to assess the declines of population mobility at the city level, and used the log-log regression model to examine the effects of population mobility declines on the disease spread measured by cumulative or new cases of COVID-19 over time after adjusting for confounders. RESULTS: The DID model showed that a continual expansion of the relative declines over time in 2020. After 4 weeks, population mobility declined by -54.81% (interquartile range, -65.50% to -43.56%). The accrued population mobility declines were associated with the significant reduction of cumulative COVID-19 cases throughout 6 weeks (ie, 1% decline of population mobility was associated with 0.72% [95% CI: 0.50%-0.93%] reduction of cumulative cases for 1 week, 1.42% 2 weeks, 1.69% 3 weeks, 1.72% 4 weeks, 1.64% 5 weeks, and 1.52% 6 weeks). The impact on the weekly new cases seemed greater in the first 4 weeks but faded thereafter. The effects on cumulative cases differed by cities of different population sizes, with greater effects seen in larger cities. CONCLUSIONS: Persistent population mobility restrictions are well deserved. Implementation of mobility restrictions in major cities with large population sizes may be even more important.

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.

Differences in the clinical characteristics and outcomes of COVID-19 patients in the epicenter and peripheral areas of the pandemic from China: a retrospective, large-sample, comparative analysis.

BACKGROUND: There is limited information on the difference in epidemiology, clinical characteristics and outcomes of the initial outbreak of the coronavirus disease (COVID-19) in Wuhan (the epicenter) and Sichuan (the peripheral area) in the early phase of the COVID-19 pandemic. This study was conducted to investigate the differences in the epidemiological and clinical characteristics of patients with COVID-19 between the epicenter and peripheral areas of pandemic and thereby generate information that would be potentially helpful in formulating clinical practice recommendations to tackle the COVID-19 pandemic. METHODS: The Sichuan & Wuhan Collaboration Research Group for COVID-19 established two retrospective cohorts that separately reflect the epicenter and peripheral area during the early pandemic. The epidemiology, clinical characteristics and outcomes of patients in the two groups were compared. Multivariate regression analyses were used to estimate the adjusted odds ratios (aOR) with regard to the outcomes. RESULTS: The Wuhan (epicenter) cohort included 710 randomly selected patients, and the peripheral (Sichuan) cohort included 474 consecutive patients. A higher proportion of patients from the periphery had upper airway symptoms, whereas a lower proportion of patients in the epicenter had lower airway symptoms and comorbidities. Patients in the epicenter had a higher risk of death (aOR=7.64), intensive care unit (ICU) admission (aOR=1.66), delayed time from illness onset to hospital and ICU admission (aOR=6.29 and aOR=8.03, respectively), and prolonged duration of viral shedding (aOR=1.64). CONCLUSIONS: The worse outcomes in the epicenter could be explained by the prolonged time from illness onset to hospital and ICU admission. This could potentially have been associated with elevated systemic inflammation secondary to organ dysfunction and prolonged duration of virus shedding independent of age and comorbidities. Thus, early supportive care could achieve better clinical outcomes.

Hypertension is a risk factor for adverse outcomes in patients with coronavirus disease 2019: a cohort study.

BACKGROUND: Comorbidities are commonly seen in patients with coronavirus disease 2019 (COVID-19), but the clinical implication is not yet well-delineated. We aim to characterize the prevalence and clinical implications of comorbidities in patients with COVID-19. METHODS: This is a retrospective multi-centre study involving patients admitted between January 16th and March 10th 2020. The composite endpoint was defined as the presence of at least one of the following, intensive care unit (ICU) admission, or the need for mechanical ventilation, or death. RESULTS: A total of 472 consecutive cases admitted to 51 certified COVID-19 tertiary care hospitals were enrolled (median age was 43 [32-53.5] years and 53.0% were male). There were 101 (21.4%) patients presented with comorbidities, including hypertension (15.0%), diabetes mellitus (7.8%), coronary artery disease (2.6%), chronic obstructive pulmonary disease (1.3%) and cerebrovascular disease (1.9%). The composite endpoint occurred in 65 (13.8%) patients. Multivariate stepwise logistic regression analysis indicated that older age (odds ratio [OR] 1.39, 95% confidence interval (CI) 1.05-1.85, per 10-year increment), antecedent hypertension (OR 2.82, 95% CI 1.09-7.29), neutrophil counts (OR 1.33, 95% CI 1.14-1.56) and lactate dehydrogenase level (OR 1.01, 95% CI 1.00-1.01) were independently associated with the presence of composite endpoint. Hypertensive patients, compared with controls, had a greater chance of experiencing the composite endpoint (p < .001) and each individual endpoint, i.e. ICU admission (p < .001), mechanical ventilation (p < .001) and death (p = .012). In the stepwise regression analysis of anti-hypertensive medications, none of the therapy predicted the composite endpoint. CONCLUSIONS: Hypertension is a common comorbidity in patients with COVID-19 and associated with adverse outcomes. KEY MESSAGES Hypertension was identified as the comorbidity associated with the prognosis of COVID-19 in this retrospective cohort. Patients with hypertension could experience an increased risk of the composite endpoint. Anti-hypertensive therapy did not affect patient outcomes.

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis.

OBJECTIVE: We sought to explore the prevalence and immediate clinical implications of acute myocardial injury in a cohort of patients with COVID-19 in a region of China where medical resources are less stressed than in Wuhan (the epicentre of the pandemic). METHODS: We prospectively assessed the medical records, laboratory results, chest CT images and use of medication in a cohort of patients presenting to two designated covid-19 treatment centres in Sichuan, China. Outcomes of interest included death, admission to an intensive care unit (ICU), need for mechanical ventilation, treatment with vasoactive agents and classification of disease severity. Acute myocardial injury was defined by a value of high-sensitivity troponin T (hs-TnT) greater than the normal upper limit. RESULTS: A total of 101 cases were enrolled from January to 10 March 2020 (average age 49 years, IQR 34-62 years). Acute myocardial injury was present in 15.8% of patients, nearly half of whom had a hs-TnT value fivefold greater than the normal upper limit. Patients with acute myocardial injury were older, with a higher prevalence of pre-existing cardiovascular disease and more likely to require ICU admission (62.5% vs 24.7%, p=0.003), mechanical ventilation (43.5% vs 4.7%, p<0.001) and treatment with vasoactive agents (31.2% vs 0%, p<0.001). Log hs-TnT was associated with disease severity (OR 6.63, 95% CI 2.24 to 19.65), and all of the three deaths occurred in patients with acute myocardial injury. CONCLUSION: Acute myocardial injury is common in patients with COVID-19 and is associated with adverse prognosis.