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.

Field-based evidence of changes in household PM2.5 and exposure during the 2020 national quarantine in China

Air pollution exposure depends not only on outdoor but also on indoor air quality and human activities. The outbreak of coronavirus in 2019 occurred close to the Spring Festival in China, when many rural-to-urban workers moved to their hometowns, resulting in increased household (HH) consumption of solid fuels for space heating in the rural north. In this study, field measurements of HH PM2.5 (particulate matter with an aerodynamic size ⩽2.5 μm) from a rural village were performed to evaluate changes in indoor, outdoor, and total exposure during the quarantine. Both indoor and outdoor PM2.5 were, as expected, higher during the heating period than during the non-heating period, resulting in much more exposure during the heating season. Indoor exposure accounted for up to 87% and 95% of the total PM2.5 exposure during the non-heating and heating periods, respectively. The contributions of indoor exposure associated with internal sources were 46% and 66%, respectively. Indoor coal combustion resulted in an increment of about 62 ± 12 μg m−3 in indoor PM2.5 exposure. Due to the quarantine, the indoor-originated PM2.5 exposure increased by 4 μg m−3 compared to that during the heating period before the lockdown. In comparison with the exposure before the quarantine during the heating period, the outdoor exposure decreased by 5 μg m−3 during the quarantine, which was mainly attributable to much less time spent outdoors, although the outdoor PM2.5 levels increased from 86 ± 49 μg m−3 to 104 ± 85 μg m−3. However, the overall exposure increased by 13 μg m−3 during the quarantine, resulting from the changes in outdoor exposure (−5 μg m−3), outdoor-originated indoor PM2.5 exposure (+9 μg m−3), PM2.5 from indoor sources before the quarantine (+5 μg m−3), and quarantine-induced indoor PM2.5 increments (+4 μg m−3). The increase in air pollution exposure during quarantine deepened concerns about the issue of HH air pollution and the clean HH energy transition actions required to eliminate traditional solid fuels.

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.