RESUMEN
The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with leads revealed that the residues E164 and Q269 around the S2 site are critical for improving the inhibitor\'s potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 M, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitor is a promising SARS-CoV-2 therapy.
Asunto(s)
COVID-19RESUMEN
We report the clinical features of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a family setting of 13 people with person-to-person transmission in Yancheng, Jiangsu Province, China.
RESUMEN
Water is essential for a sustainable economic prosperity, but rapid economic growth and intensive agricultural activities usually cause water pollution. The middle and lower reaches of China’s Yangtze River Basin were urbanized and industrialized much earlier than the upper reach and have been suffering from water pollution. In the past two decades, economic growth accelerated in the upper reach due to several national economic initiatives. Based on analyzing water quality changes from 2000 to 2019 and during the COVID-19 lockdown in 2020 for Chengdu in the upper reach, we hope to provide some water governance suggestions. In 2019, water at 66% of 93 sites in Chengdu did not achieve the national III standards using measurements of 23 water quality parameters. The top two pollutants were total nitrogen (TN) and fecal coliform (FC). From 2000 to 2019, water quality was not significantly improved at the non-background sites of Chengdu's Min Basin, and the pollution in this basin was mainly from local pollutants release. During the same period, water quality deteriorated in Chengdu’s Tuo Basin, where pollution was the result of pollutant discharges in Chengdu in addition to inter-city pollutant transport. During the COVID-19 lockdown, water quality generally improved in the Min Basin but not in the Tuo Basin. A further investigation on which pollution sources were shut down or not during the lockdown can help make pollution reduction targets. Based on the results, we provide suggestions to strengthen inter-jurisdictional and inter-institutional cooperation, water quality monitoring and evaluation, and ecological engineering application.