Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease.

RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity. We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.

Willingness to accept COVID-19 vaccine among the elderly and the chronic disease population in China.

A cross-sectional field survey was conducted from November 2020 to January 2021 among 7259 participants to investigate the public perception, willingness, and information sources for COVID-19 vaccination, with the focus on the elderly and non-communicable chronic disease (NCD) population. Multiple logistic regressions were performed to identify associated factors of the vaccination willingness. The willingness rate of the elderly to accept the future COVID-19 vaccine (79.08%) was lower than that of the adults aged 18-59 (84.75%). The multiple analysis didn't identify significant relationship between NCD status and the vaccination intention. The main reasons for vaccine hesitancy by the public were: concern for vaccine safety, low infection risk, waiting and seeing others getting vaccinated, concern of vaccine effectiveness and price. Their relative importance differed between adults aged 18-59 and the elderly, and between adults aged 18-59 with or without NCD. Perception for vaccination importance, vaccine confidence, and trust in health workers were significant predictors of the vaccination intention in both age groups. The elderly who perceived high infection risk or had trust in governments were more likely to accept the vaccine. Compared with the adults aged 18-59, the elderly used fewer sources for COVID-19 vaccination information and more trusted in traditional media and family, relatives, and friends for getting vaccination recommendations. To promote vaccine uptake, the vaccination campaigns require comprehensive interventions to improve vaccination attitude, vaccine accessibility and affordability, and tailor strategies to address specific concerns among different population groups and conducted via their trusted sources, especially for the elderly.

The Changing Acceptance of COVID-19 Vaccination in Different Epidemic Phases in China: A Longitudinal Study.

COVID-19 vaccines have been conditionally used in a few countries, including China since December 2020. The present study aimed to examine whether the acceptance of COVID-19 vaccination changed in different COVID-19 epidemic phases in China. Two consecutive surveys were conducted among Chinese adults in March (n = 2058) (severe epidemic phase) and November-December (n = 2013) (well-contained phase, right before the COVID-19 vaccine was conditionally approved) 2020, and 791 respondents were longitudinally followed-up. The attitude, acceptance, and preferences for future COVID-19 vaccination were compared between two epidemic phases. Multivariate logistic regression was used to identify influencing factors of acceptance. Among the 791 respondents longitudinally followed, 91.9% in March and 88.6% of them in November-December 2020 would like to get COVID-19 vaccination in China. In March 58.3% wished to get vaccinated immediately, but the proportion declined to 23.0% in November-December 2020, because more respondents wanted to delay vaccination until the vaccine's safety was confirmed. Similar results were found by comparing all respondents from the two cross-sectional surveys in different epidemic phases. The risk perception, attitude for the importance of vaccination against COVID-19, vaccination history, valuing doctor's recommendations, vaccination convenience, or vaccine price in decision-making had impacts on respondents' intention for immediate vaccination. The public acceptance for COVID-19 vaccination in China sustained at a high level in different COVID-19 epidemic phases. However, the intention of immediate vaccination declined substantially due to concerns about the vaccine's safety. Information about vaccination safety from authoritative sources, doctor's recommendations, and vaccination convenience were important in addressing vaccine hesitancy and promoting successful herd immunity for the general population in China.