High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

Experience of clinical nurses engaged in caring for patients with COVID-19: A qualitative systematic review and meta-synthesis.

AIMS AND OBJECTIVE: This qualitative review summarises and synthesises the available evidence on subjective experiences of clinical nurses who cared for patients with COVID-19. BACKGROUND: Nurses are first responders and play a vital role in emerging infectious disease epidemics such as the COVID-19 pandemic. In this context, they also face many difficulties and challenges related, for example to the imbalance between extensive demands and low control over work tasks. DESIGN AND METHOD: A systematic review of qualitative studies and meta-synthesis focused on the experiences of clinical nurses caring for patients with COVID-19 during the pandemic was carried out. RESULTS: A total of 279 findings were extracted, aggregated into 21 categories and combined into seven synthesised findings, namely (1) professional nursing practice during the pandemic, (2) support systems, (3) somatic sensations and psychological experiences, (4) difficulties and challenges, (5) coping strategies and behaviour, (6) impact on life, profession and values, and (7) needs and expectations for the future. CONCLUSION: Nurses encountered considerable difficulties and challenges in caring for patients with COVID-19. Nurses caring for patients with COVID-19 need more support from organisations, families and society. It is essential to explore positive coping strategies suitable for working in different cultural backgrounds. Policymakers and decision-makers should pay attention to the experiences and voices of nurses. RELEVANCE TO CLINICAL PRACTICE: It is critical for nurse managers to consider how to enhance the support system and help nurses develop adaptive coping strategies in response to COVID-19. Nurses' experiences and voices are valuable in improving health emergency response systems. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution.

Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants.

The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants of infection are vastly different across the studied models and conditions, imposing challenges for host-based antiviral drug discovery. Based on the postulation that antiviral drugs tend to reverse the global host gene expression induced by viral infection, we retrospectively evaluated hundreds of signatures derived from 1,700 published host transcriptomic profiles of SARS/MERS/SARS-CoV-2 infection using an iterative data-driven approach. A few of these signatures could be reversed by known anti-SARS-CoV-2 inhibitors, suggesting the potential of extrapolating the biology for new variant research. We discovered IMD-0354 as a promising candidate to reverse the signatures globally with nanomolar IC50 against SARS-CoV-2 and its five variants. IMD-0354 stimulated type I interferon antiviral response, inhibited viral entry, and down-regulated hijacked proteins. This study demonstrates that the conserved coronavirus signatures and the transcriptomic reversal approach that leverages polypharmacological effects could guide new variant therapeutic discovery.

Drug target inference by mining transcriptional data using a novel graph convolutional network framework

A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or off-target effects. Recently, the fast accumulation of gene transcriptional profiling data provides us an unprecedented opportunity to explore the protein targets of chemical compounds from the perspective of cell transcriptomics and RNA biology. Here, we propose a novel Siamese spectral-based graph convolutional network (SSGCN) model for inferring the protein targets of chemical compounds from gene transcriptional profiles. Although the gene signature of a compound perturbation only provides indirect clues of the interacting targets, and the biological networks under different experiment conditions further complicate the situation, the SSGCN model was successfully trained to learn from known compound-target pairs by uncovering the hidden correlations between compound perturbation profiles and gene knockdown profiles. On a benchmark set and a large time-split validation dataset, the model achieved higher target inference accuracy as compared to previous methods such as Connectivity Map. Further experimental validations of prediction results highlight the practical usefulness of SSGCN in either inferring the interacting targets of compound, or reversely, in finding novel inhibitors of a given target of interest. Supplementary Information The online version contains supplementary material available at 10.1007/s13238-021-00885-0.

Structure-Based Virtual Screening and Identification of Potential Inhibitors of SARS-CoV-2 S-RBD and ACE2 Interaction.

The emergence and rapid spread of SARS-CoV-2 have caused a worldwide public health crisis. Designing small molecule inhibitors targeting SARS-CoV-2 S-RBD/ACE2 interaction is considered as a potential strategy for the prevention and treatment of SARS-CoV-2. But to date, only a few compounds have been reported as SARS-CoV-2 S-RBD/ACE2 interaction inhibitors. In this study, we described the virtual screening and experimental validation of two novel inhibitors (DC-RA016 and DC-RA052) against SARS-CoV-2 S-RBD/ACE2 interaction. The NanoBiT assays and surface plasmon resonance (SPR) assays demonstrated their capabilities of blocking SARS-CoV-2 S-RBD/ACE2 interaction and directly binding to both S-RBD and ACE2. Moreover, the pseudovirus assay revealed that these two compounds possessed significant antiviral activity (about 50% inhibition rate at maximum non-cytotoxic concentration). These results indicate that the compounds DC-RA016 and DC-RA052 are promising inhibitors against SARS-CoV-2 S-RBD/ACE2 interaction and deserve to be further developed.

Willingness to participate in front-line work during the COVID-19 pandemic: A cross-sectional study of nurses from a province in South-West China.

AIM: To explore the current status of Chinese nurses' willingness to work during the COVID-19 pandemic and the factors that influence them. BACKGROUND: The demand for front-line nurses continues to grow during the COVID-19 pandemic, but their willingness varies significantly. Therefore, it is crucial to explore nurses' willingness to report for front-line work. METHODS: A cross-sectional study of 1,310 nurses from six tertiary hospitals was conducted. The participants completed self-administered online questionnaires. RESULTS: A total of 90.5% of nurses reported that they would like to voluntarily participate in front-line work. Those with previous training, higher self-efficacy scores, and lower perceived risk and self-worth scores were more likely to participate in front-line work, while nurses, who had 11-15 years of work experience and were worried about their family and the lack of family support, were less likely to be involved in front-line work. CONCLUSION: This study found that the vast majority of nurses were willing to participate in front-line work and affirmed the positive effects of previous infection prevention training, self-efficacy and self-worth. IMPLICATIONS FOR NURSING MANAGEMENT: This research emphasizes the necessity of infection prevention training and provides evidence for further emergency workforce deployment and incentives.