Two Binding Sites of SARS-CoV-2 Macrodomain 3 Probed by Oxaprozin and Meclomen.

Severe acute respiratory syndrome-coronavirus-1/2 (SARS-CoV-1/2) macrodomain 3 (Mac3) is critical for replication and transcription of the viral genome and is therefore a potential therapeutic target. Here, we solved the crystal structure of SARS-CoV-2 Mac3, which reveals a small-molecule binding pocket. Two low-molecular-weight drugs, oxaprozin and meclomen, induced different patterns of nuclear magnetic resonance (NMR) chemical shift perturbations (CSPs). Meclomen binds to site I of SARS-CoV-2 Mac3 with binding pose determined by NMR CSP and transferred paramagnetic relaxation enhancement, while oxaprozin binds to site II as revealed by the crystal structure. Interestingly, oxaprozin and meclomen both perturb residues in site I of SARS-CoV Mac3. Fluorescence polarization experiments further demonstrated that oxaprozin and meclomen inhibited the binding of DNA-G4s to SARS-CoV-2 Mac3. Our work identified two adjacent ligand-binding sites of SARS-CoV-2 Mac3 that shall facilitate structure-guided fragment linking of these compounds for more potent inhibitors.

5-min mindfulness audio induction alleviates psychological distress and sleep disorders in patients with COVID-19.

BACKGROUND: Mindfulness meditation is beneficial to mitigate the negative effects of the coronavirus disease 2019 (COVID-19) pandemic in the general population, but no study examined such meditation in the COVID-19 patients themselves. AIM: To explore the short-term efficacy of mindfulness meditation in alleviating psychological distress and sleep disorders in patients with COVID-19. METHODS: This prospective study enrolled patients with mild COVID-19 treated at Wuhan Fangcang Hospital in February 2020. The patients were voluntarily divided into either a mindfulness or a conventional intervention group. The patients were evaluated before/after the intervention using the Short Inventory of Mindfulness Capability (SMI-C), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: Seventy-five participants were enrolled in this study, with 43 and 32 in the mindfulness and conventional groups, respectively. Before the intervention, there were no differences in SMI-C, HADS, or PSQI scores between the two groups. After the 2-wk intervention, the mindfulness level (from 30.16 ± 5.58 to 35.23 ± 5.95, P < 0.001) and sleep quality (from 12.85 ± 3.06 to 9.44 ± 3.86, P < 0.001) were significantly increased in the mindfulness group. There were no differences in the conventional group. After the intervention, the mindfulness level (35.23 ± 5.95 vs 31.17 ± 6.50, P = 0.006) and sleep quality (9.44 ± 3.86 vs 11.87 ± 4.06, P = 0.011) were significantly higher in the mindfulness group than in the conventional group. Depression decreased in the mindfulness group (from 14.15 ± 3.21 to 12.50 ± 4.01, P = 0.038), but there was no difference between the two groups. CONCLUSION: Short-term mindfulness meditation can increase the mindfulness level, improve the sleep quality, and decrease the depression of patients with COVID-19.