Acriflavine and proflavine hemisulfate as potential antivirals by targeting Mpro.

The evolving SARS-CoV-2 epidemic buffets the world, and the concerted efforts are needed to explore effective drugs. M^pro is an intriguing antiviral target for interfering with viral RNA replication and transcription. In order to get potential anti-SARS-CoV-2 agents, we established an enzymatic assay using a fluorogenic substrate to screen the inhibitors of M^pro. Fortunately, Acriflavine (ACF) and Proflavine Hemisulfate (PRF) with the same acridine scaffold were picked out for their good inhibitory activity against M^pro with IC₅₀ of 5.60 ± 0.29 µM and 2.07 ± 0.01 µM, respectively. Further evaluation of MST assay and enzymatic kinetics experiment in vitro showed that they had a certain affinity to SARS-CoV-2 M^pro and were both non-competitive inhibitors. In addition, they inhibited about 90 % HCoV-OC43 replication in BHK-21 cells at 1 µM. Both compounds showed nano-molar activities against SARS-CoV-2 virus, which were superior to GC376 for anti-HCoV-43, and equivalent to the standard molecule remdesivir. Our study demonstrated that ACF and PRF were inhibitors of M^pro, and ACF has been previously reported as a PL^pro inhibitor. Taken together, ACF and PRF might be dual-targeted inhibitors to provide protection against infections of coronaviruses.

Psychological Effect of Discrete Outbreak Events of COVID-19 on Health Information Search in China.

Community transmission events occasionally happened in the long-term pandemic, which led to repeated outbreaks of COVID-19. In addition to potential physical threats, the outbreaks could also lead to psychological stress and influence their health behaviors, especially for vulnerable people. It poses a great challenge to both physical and mental health management. However, little is known about the impacts of discrete outbreak events of COVID-19 on people's reactions to health concerns in the long-term pandemic period. In the current study, we discussed the impact of discrete outbreak events of COVID-19 on health information search for specific symptoms in China from a perceptive of susceptibility. The empirical study was conducted after the first wave of outbreak events ended in China from June to October 2020. Three typical outbreak events happened during this period, and a total of 1800 search index data for 60 cities in China crawled from Baidu search engine were included in the data set. Using the real-world searching data, we conducted a panel data analysis to examine the psychological effect of discrete outbreak events on the symptom search and the moderation effect of the geographical distance. It was found that discrete outbreak events significantly increased the symptom search, and its impacts were various in different regions. More health information search caused by discrete outbreak events was found in cities which were closer to the outbreak area. Implications for healthcare were discussed.

Erythromycin Estolate Is a Potent Inhibitor Against HCoV-OC43 by Directly Inactivating the Virus Particle.

In addition to antibacterial effects, macrolide antibiotics exhibit other extensive pharmacological effects, such as anti-inflammatory and antiviral activities. Erythromycin estolate, one of the macrolide antibiotics, was previously investigated to effectively inhibit infections of various flaviviruses including Zika virus, dengue virus, and yellow fever virus, but its antiviral effect against human coronavirus remains unknown. Thus, the current study was designed to evaluate the antiviral efficacy of erythromycin estolate against human coronavirus strain OC43 (HCoV-OC43) and to illustrate the underlying mechanisms. Erythromycin estolate effectively inhibited HCoV-OC43 infection in different cell types and significantly reduced virus titers at safe concentration without cell cytotoxicity. Furthermore, erythromycin estolate was identified to inhibit HCoV-OC43 infection at the early stage and to irreversibly inactivate virus by disrupting the integrity of the viral membrane whose lipid component might be the target of action. Together, it was demonstrated that erythromycin estolate could be a potential therapeutic drug for HCoV-OC43 infection.

Vaccination of cats with Sad23L-nCoV-S vaccine candidate against major variants of SARS-CoV-2.

Cats are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and risk transmitting viruses to naive cats or humans. Here, based on our novel adenovirus-vectored COVID-19 vaccine, the immunogenicity of Sad23L-nCoV-S vaccine was evaluated in cats by prime-boost vaccinations. Five cats were primed with a dose of 108 plaque-forming units (PFUs) Sad23L-nCoV-S vaccine and then boosted with an equal dose of same vaccine at a 4-week interval. Cat serum neutralizing antibody (NAb) titers (the sample dilution at which 50% inhibitory concentration [IC50]) were measured as IC50 15,849 to wild-type strain, IC50 6,591 to Alpha, IC50 2,315 to Beta, IC50 2,744 to Gamma, IC50 1,848 to Delta, and IC50 318 to Omicron variants of pseudotyped SARS-CoV-2 viruses at week 6 post-prime vaccination. All NAb levels to these five variants were ≥IC50 49 from vaccinated cats at week 10, while 48.8% to Delta and 100% to Omicron variants were

Photocatalytic Chemical Crosslinking for Profiling RNA–Protein Interactions in Living Cells

The dynamic interactions between RNAs and proteins play crucial roles in regulating diverse cellular processes. Proteome‐wide characterization of these interactions in their native cellular context remains desirable but challenging. Herein, we developed a photocatalytic crosslinking (PhotoCAX) strategy coupled with mass spectrometry (PhotoCAX‐MS) and RNA sequencing (PhotoCAX‐seq) for the study of the composition and dynamics of protein‐RNA interactions. By integrating the blue light‐triggered photocatalyst with a dual‐functional RNA–protein crosslinker (RP‐linker) and the phase separation‐based enrichment strategy, PhotoCAX‐MS revealed a total of 2044 RBPs in human HEK293 cells. We further employed PhotoCAX to investigate the dynamic change of RBPome in macrophage cells upon LPS‐stimulation, as well as the identification of RBPs interacting directly with the 5′ untranslated regions of SARS‐CoV‐2 RNA. [ FROM AUTHOR] Copyright of Angewandte Chemie International Edition 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 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 . (Copyright applies to all s.)

Montelukast Inhibits HCoV-OC43 Infection as a Viral Inactivator.

Coronaviruses (CoVs) consist of a large group of RNA viruses causing various diseases in humans and in lots of animals. Human coronavirus (HCoV) OC43, the prototype of beta-coronavirus discovered in the 1960s, has been circulating in humans for long time, and infection with other emerging strains of beta-coronavirus (SARS-CoV, SARS-CoV-2, and MERS-CoV) can lead to severe illness and death. In this study, we found that montelukast, a leukotriene receptor antagonist, potently inhibited the infection of HCoV-OC43 in distinct cells in a dose- and time- dependent manner. Additionally, the results showed that montelukast induced release of HCoV-OC43 genomic RNA by disrupting the integrity of the viral lipid membrane, and irreversibly inhibited viral infection. Considering the similarity among HCoV-OC43, MERS-CoV, and SARS-CoV-2, it suggests that montelukast may be a potential candidate for the treatment of human beta-coronavirus infection.

Reusable Cu2-xS-modified masks with infrared lamp-driven antibacterial and antiviral activity for real-time personal protection.

Disposable surgical masks are widely used by the general public since the onset of the coronavirus outbreak in 2019. However, current surgical masks cannot self-sterilize for reuse or recycling for other purposes, resulting in high economic and environmental costs. To solve these issue, herein we report a novel low-cost surgical mask decorated with copper sulfide (Cu2-xS) nanocrystals for photothermal sterilization in a short time (6 min). With the spun-bonded nonwoven fabrics (SNF) layer from surgical masks as the substrate, Cu2-xS nanocrystals are in-situ grown on their surface with the help of a commercial textile adhesion promoter. The SNF-Cu2-xS layer possesses good hydrophobicity and strong near infrared absorption. Under the irradiation with an infrared baking lamp (IR lamp, 50 mW cm-2), the surface temperature of SNF-Cu2-xS layer on masks can quickly increase to over 78 °C, resulting from the high photothermal effects of Cu2-xS nanocrystals. As a result, the polluted masks exhibit an outstanding antibacterial rate of 99.9999% and 85.4% for the Escherichia coli (E.coli) and Staphylococcus aureus (S. aureus) as well as the inactivation of human coronavirus OC43 (3.18-log10 decay) and influenza A virus A/PR/8/34 (H1N1) (3.93-log10 decay) after 6 min irradiation, and achieve rapid sterilization for reuse and recycling. Therefore, such Cu2-xS-modified masks with IR lamp-driven antibacterial and antiviral activity have great potential for real-time personal protection.

Ultra-fast bacterial inactivation of Cu2O@Halloysite nanotubes hybrids with charge adsorption and physical piercing ability for medical protective fabrics

Metals have been used for wound treatment and toxicity testing since ancient times. With the development of nanotechnology, metal oxides have been proven to have excellent sterilization and disinfection functions. However, the rapid bacterial inactivation efficiency and trapping physicochemical killing ability remain simultaneously undemonstrated in antibacterial nanohybrids. Here, we demonstrate a method for in-situ reduction of small-sized Cu2O particles on one-dimensional inorganic halloysite nanotubes (HNTs). The resultant Cu2O@HNTs hybrids not only give Cu2O excellent dispersibility, but also exert the synergistic effect of the charge adsorption of metal oxides and the physical piercing effect of the small-sized nanotubes. Furthermore, the release of Cu2+ from hybrids damages cell membranes and denatures proteins and DNA. Through this sterilization mechanism, Cu2O@HNTs allow for the inactivation rate of Escherichia coli to reach 94.5% within 2 min and complete inactivation within 10 min. This excellent sterilization mode makes Cu2O@HNTs exhibit excellent broad-spectrum antibacterial activity and inactivation efficiency, while shows weak cytotoxicity. These hybrids were further applied in the processing of functional antibacterial fibers and fabrics. Thus, we believe that this excellent antibacterial hybrid is practically attractive in this critical time of the COVID-19 pandemic.

EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations.

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.

A Self-Biomineralized Novel Adenovirus Vectored COVID-19 Vaccine for Boosting Immunization of Mice.

SARS-CoV-2 has caused more than 3.8 million deaths worldwide, and several types of COVID-19 vaccines are urgently approved for use, including adenovirus vectored vaccines. However, the thermal instability and pre-existing immunity have limited its wide applications. To circumvent these obstacles, we constructed a self-biomineralized adenovirus vectored COVID-19 vaccine (Sad23L-nCoV-S-CaP) by generating a calcium phosphate mineral exterior (CaP) based on Sad23L vector carrying the full-length gene of SARS-CoV-2 spike protein (S) under physiological condition. This Sad23L-nCoV-S-CaP vaccine was examined for its characteristics of structure, thermostability, immunogenicity and avoiding the problem of preexisting immunity. In thermostability test, Sad23L-nCoV-S-CaP could be stored at 4 °C for over 45 days, 26 °C for more than 8 days and 37 °C for approximately 2 days. Furthermore, Sad23L-nCoV-S-CaP induced higher level of S-specific antibody and T cell responses, and was not affected by the pre-existing anti-Sad23L immunity, suggesting it could be used as boosting immunization on Sad23L-nCoV-S priming vaccination. The boosting with Sad23L-nCoV-S-CaP vaccine induced high titers of 105.01 anti-S1, 104.77 anti-S2 binding antibody, 103.04 pseudovirus neutralizing antibody (IC50), and robust T-cell response of IFN-γ (1466.16 SFCs/106 cells) to S peptides, respectively. In summary, the self-biomineralization of the COVID-19 vaccine Sad23L-nCoV-S-CaP improved vaccine efficacy, which could be used in prime-boost regimen for prevention of SARS-CoV-2 infection in humans.

Track-etched membrane microplate and smartphone immunosensing for SARS-CoV-2 neutralizing antibody.

The level of neutralizing antibody (NAb) to SARS-CoV-2 could be used to evaluate the acquired protective immunity of COVID-19 patients or vaccinees. Here we develop a track-etched microporous membrane filtration microplate (TEM) and optical fibers transmitted immunosensing smartphone platform (TEMFIS) based surrogate virus neutralization test (TEMFIS-sVNT) for rapid one-step testing of NAb to SARS-CoV-2. Coefficient variation (CV) of intra-assay and inter-assay precisions of TEMFIS-sVNT varied below 9% or 14%, respectively. By agreement with pseudovirus neutralization test (pVNT) and ELISA-sVNT for testing of serum samples from 41 COVID-19 patients, 50 COVID-19 vaccinees and 320 healthy blood donors (P = 0.895), TEMFIS-sVNT detected the NAb positivity (sensitivity) in 92.68% COVID-19 patients and 76% vaccinees, but the NAb negativity (specificity) in 100% blood donors. In conclusion, TEMFIS-sVNT can be used for quantitatively point-of-care testing of neutralizing antibody to SARS-CoV-2 in blood samples from COVID-19 patients and vaccinees.

The impact of the COVID-19 pandemic on firms: a survey in Guangdong Province, China.

Background: The COVID-19 pandemic has affected all sectors of the world economy and society. To understand the impact of the pandemic on firms in China and suggest public policies to deal with the negative effects, we investigated firms in Guangdong Province. Methods: The survey sample included 524 firms in 15 cities in Guangdong Province. We chose these firms from the list published by the government, considering the industrial characteristics of Guangdong province and firm size. The questionnaire was developed based on previous studies carried out by UNDP. It comprised four categories with a total of 17 questions. The executives of firms were contacted by telephone or WeChat, and were invited to answer self-administered questionnaires through an online survey platform. The data was analyzed by SPSS. Results: The following key findings were revealed through the survey: (1) 48.7% of firms maintained stability, and 35.1% experienced a halt in operation or faced closure; (2) Nearly 70-90% already exploit online commerce or are willing to do so, and also remote office work, and digital operations. (3) 46% believe that they will certainly incur losses for 2020, and 83.5% expect the city's GDP to decrease. Conclusions: Firms in Guangdong Province have faced great challenges in the epidemic. Their production and operation activities have been limited, and they are facing significant risks. It is necessary to implement policies that would profoundly lower production costs for firms, help them survive this difficult period, and gradually return to normal business.