Children with allergic asthma sensitized to house dust mites getting better health during COVID-19 pandemic (preprint)

Background: Since December 2019, 2019 novel corona virus (2019-nCov) disease (COVID-19) has extended to most parts of China with more than 80 thousand cases. From Feb 1 to Mar 31 of 2020, all children were asked to stay indoors in China. Then how it affected allergic asthma (AA) sensitized to house dust mites (HDM) in children was interestingly to clarify. Objective: To investigate the changes of clinical characteristics of children with AA sensitized to HDM during COVID-19 pandemic. Method: The data including asthma symptom scores(SS), visual analog scores (VAS), asthma quality of life questionnaire (AQLQ) and medicine scores (MS) as well as respiratory infections, cares, staying up late and diets, collected from children with AA sensitized to HDM from Feb 1 to Mar 31 of 2019 and 2020 retrospectively, were analyzed. Results: There were 85 children with AA sensitized to HDM included in this research. Compared with SS, VAS, AQLQ and MS of the patients from Feb 1 to Mar 31 of 2019, SS, VAS, AQLQ and MS of the patients improved significantly (p<0.05) during COVID-19 pandemic. No respiratory infections occurred among them and they got better cares, had better diets and stayed up late less during COVID-19 pandemic. Conclusion: During COVID-19 pandemic, children with AA sensitized to HDM got better health for staying indoors, which might be associated with no respiratory infections, better cares, better diets and less staying up late.

The humanized nanobody RBD-1-2G tolerates the spike N501Y mutation to neutralize SARS-CoV-2 (preprint)

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.

A hybrid in silico approach reveals novel inhibitors of multiple SARS-CoV-2 variants (preprint)

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytophatic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (~16% of predicted hits) active compounds (Efficacy > 30%, IC50 [≤] 15 M). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further analysis identified allosteric binders to host receptor angiotensin-converting enzyme 2, which were able to inhibit the entry of pseudoparticles bearing spike protein of wild type SARS-CoV-2 as well as South African B.1.351 and UK B.1.1.7 variants.

Psychological distress and its correlates among COVID-19 survivors during early convalescence across age groups

Objective: To examine the psychological distress and the associated predictor factors of the 2019 corona-virus disease (COVID-19) on survivors in the early convalescence in Shenzhen. Method: A survey questionnaire consisting of post-traumatic stress disorder self-rating scale (PTSD-SS), self-rating depression scale (SDS), and self-rating anxiety scale (SAS) was presented to COVID-19 survivors still in quarantine. Scores of each scale and subscale were dependent variables in the Mann-Whitney test and stepwise regression analysis. Results: A total of 126 subjects were included in the study, the mean scores of PTSD-SS, SDS, and SAS were 45.5 +/- 18.9, 47.3 +/- 13.1, and 43.2 +/- 10.2, respectively, meanwhile, 9 (31.0%), 28 (22.2%), and 48 (38.1%) of the survivors met the cut-score for clinical significant symptoms of stress response, anxiety, and depression, respectively. Infected family members, and postinfection physical discomforts were significantly associated with scores on all three scales. Social support, retirement, and being female had significant associations with the PTSD-SS score. The survivors aged 60 or above experienced less severe stress response symptoms, fewer emotional symptoms of depression, and fewer anxiety symptoms than younger survivors. Conclusion: The occurrence rate of psychological distress among the COVID-19 survivors in early convalescence was high, highlighting the need for all COVID-19 survivors to be screened for psychological distress regularly for timely intervention. The predictors indicated by the current study may help to identify those at high-risk. Besides, the results indicated the older survivors suffered less emotional reactivity and fewer stress response symptoms from infectious diseases than the younger ones. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Woolen Respirators for Thermal Management

COVID‐19 pandemic recently has a great impact on personalized protection and healthcare, especially in the area of the respiratory mask. However, due to the complex relationship between filtration performance and thermal management, there is a lack of investigation considering both characters in respirators. Woolen knitwears are recently well acknowledged as textiles for both hot and cold because of their superior water‐actuated shape memory performance. To incorporate protective function against bacteria, virus, microdroplet, and particulate matter, melt‐blown polypropylene can be introduced as a barrier layer. Herein, a robust and sustainable bio‐based woolen respirator with the superior ability of thermal management is prepared using simple knitting and melt‐blown technology. The as‐prepared respirators provide excellent protection from airborne particulate along with the high level of comfort, compared with a commercial mask. Moreover, it exhibits a high rating during wear trial. This provides a new insight to develop high quality sustainable respiratory mask with an excellent comfort performance from functional biomaterials. [ABSTRACT FROM AUTHOR] Copyright of Advanced Materials Technologies is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Non-covalent TMPRSS2 inhibitors identified from virtual screening (preprint)

The SARS-CoV-2 pandemic has prompted researchers to pivot their efforts to finding anti-viral compounds and vaccines. In this study, we focused on the human host cell transmembrane protease serine 2 (TMPRSS2), which plays an important role in the viral life cycle by cleaving the spike protein to initiate membrane fusion. TMPRSS2 is an attractive target and has received significant attention for the development of drugs against SARS and MERS. Starting with comparative structural modeling and binding model analysis, we developed an efficient pharmacophore-based approach and applied in a large-scale in silico database screening for small molecule inhibitors against TMPRSS2. A number of novel inhibitors were identified, providing starting points for further development of drug candidates for the treatment of COVID-19.

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2 (preprint)

Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

Identification of SARS-CoV-2 3CL Protease Inhibitors by a Quantitative High-throughput Screening (preprint)

Background and PurposeThe COVID-19 caused by SARS-CoV-2 has emphasized the urgent need for therapeutic development. Drug repurposing screening is the most practical and rapid approach for discovery of such therapeutics. The 3CLpro, or main protease (Mpro) of SARS-CoV-2 is a valid drug target as it is a viral enzyme with an essential role in viral replication, and cleavage specificity that is distinct from host proteases. Experimental ApproachWe employed and miniaturized a fluorogenic 3CLpro enzyme assay in which 3CLpro cleaves a quenched peptide substrate and releases a fluorescent fragment, resulting an increase in fluorescence signal. By using this SARS-CoV-2 3CLpro assay, we conducted a qHTS of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds, at 4 compound concentrations. The confirmed 3CLpro inhibitors were also tested in a SARS-CoV-2 cytopathic effect assay to determine their effects on rescuing of cell death caused by the virus infection. Key ResultsTwenty-seven small molecule inhibitors of SARS-CoV-2 3CLpro have been identified with IC50s ranging from 0.26 to 27.1 M with a greater than 80% maximal inhibition. Walrycin B (IC50 = 0.26 M), Hydroxocobalamin (IC50 = 3.29 M), Suramin sodium (IC50 = 6.50 M), Z-DEVD-FMK (IC50 = 6.81 M), and LLL-12 (IC50 = 9.84 M) are the most potent 3CLpro inhibitors with IC50s under 10 M. The activities of anti-SARS-CoV-2 viral infection were confirmed in 11 of 27 compounds. Conclusion and ImplicationsSome of the newly identified inhibitors of SARS-CoV-2 3CLpro may be used in combination therapy with other drugs for synergistic effect to treat COVID-19 patients. The other inhibitors found in this study can provide starting points for medicinal chemistry optimizations. Bullet point summaryWhat is already known O_LISARS-CoV-2 3CLpro is a valid target for drug development. C_LI What this study adds O_LIIdentification of 27 inhibitors of SARS-CoV-2 3CLpro by a qHTS of 10,755 compounds consisting of approved and investigational drugs, and bioactive compounds. C_LI Clinical significance O_LISome of the newly identified 3CLpro inhibitors can be evaluated in drug combination therapy for synergistic effect to treat COVID-19 patients, while the others can serve as starting points for medicinal chemistry optimization to improve potency and drug like properties for drug development. C_LI

An OpenData portal to share COVID-19 drug repurposing data in real time (preprint)

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign - named OpenData - with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets. The goal is to support research scientists, clinical investigators and public health officials through open data sharing and analysis tools to expedite the development of SARS-CoV-2 interventions, and to prioritize promising compounds and repurposed drugs for further development in treating COVID-19.

The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators (preprint)

SARS-CoV-2 is a new type of coronavirus capable of rapid transmission and causing severe clinical symptoms; much of which has unknown biological etiology. It has prompted researchers to rapidly mobilize their efforts towards identifying and developing anti-viral therapeutics and vaccines. Discovering and understanding the virus’ pathways of infection, host-protein interactions, and cytopathic effects will greatly aid in the design of new therapeutics to treat COVID-19. While it is known that chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including inhibiting autophagy, there are also dose-limiting toxicities in patients that make clearly establishing their potential mechanisms-of-action problematic. Therefore, we evaluated a range of other autophagy modulators to identify an alternative autophagy-based drug repurposing opportunity. In this work, we found that 6 of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero-E6 cells with EC50 values ranging from 2.0 to 13 µM and selectivity indices ranging from 1.5 to >10-fold. Immunofluorescence staining for LC3B and LysoTracker dye staining assays in several cell lines indicated their potency and efficacy for inhibiting autophagy correlated with the measurements in the SARS-CoV-2 cytopathic effect assay. Our data suggest that autophagy pathways could be targeted to combat SARS-CoV-2 infections and become an important component of drug combination therapies to improve the treatment outcomes for COVID-19.One Sentence Summary Blocking SARS-CoV-2 cytopathic effects with selective autophagy inhibitors underlying the clinical benefits of chloroquine and hydroxychloroquine.Competing Interest StatementThe authors have declared no competing interest.View Full Text