MXene‐Based Aptameric Fluorosensor for Sensitive and Rapid Detection of COVID‐19

MXene‐Based Aptameric FluorosensorsThe aptamer‐functionalized MXene nanosheet acts as an effective bionanosensor for fluorescence‐enhanced detection of COVID‐19 with high sensitivity and specificity. This fluosensor is capable of detecting SARS‐CoV‐2 spike protein (limit of detection: 38.9 fg mL−1) and SARS‐CoV‐2 pseudovirus (limit of detection: 7.2 copies) within 30 min, and can also detect clinical samples. More details can be found in article number 2301146 by Binwu Ying and co‐workers.

Investigation on KAP and satisfaction related to COVID-19 prevention and control in urban and rural residents in Zunyi city

Objective: To investigate the knowledge,attitude, and practice(KAP)related to COVID-19 and the satisfaction with the prevention and control of COVID-19 in urban and Rural Residents in Zunyi City, and provide a reference for the health education and prevention and control of COVID-19. Methods: Through online and offline questionnaires, the stratified multistage sampling method was used to investigate the KAP and satisfaction of urban and rural residents in Zunyi City for the prevention and control of the COVID-19epidemic, and to analyze the differences and influencing factors of KAP among residents with different characteristics. Results: A total of 603 valid questionnaires were collected. The total awareness rate of COVID-19 among residents was 79.43%. There was a significant difference in the awareness of COVID-19 among different ages, educational levels, and occupations(P < 0.05). The proportion of residents with a positive attitude towards COVID-19 was 87.23%, while there was no significant difference in the attitude of residents with different characteristics(P > 0.05). Moreover,93.37% of them had good behavior in preventing the COVID-19 virus, while the differences among residents with different education and occupation were statistically significant(P < 0.05). The result of multivariate analysis showed that residents with low education levels had lower cognition of COVID-19 than those with high education levels OR = 0.647(95%CI 0.548,0.764). The residents with high cognition took better protective behavior than those with low cognition OR = 0.531(95%CI 0.328,0.860). Conclusion: Urban and rural residents have a high degree of satisfaction,a good KAP, and a high level of enthusiasm for COVID-19prevention and control. However,it is necessary to strengthen the publicity and education of COVID-19 in vulnerable groups(such as low education levels and older/younger) to better promote the precise prevention and control of COVID-19.

The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis.

Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has been well-studied in several neuro-associated diseases in recent years. In the present study, we found that CH24H expression can be induced by several neuroinvasive viruses, including vesicular stomatitis virus (VSV), rabies virus (RABV), Semliki Forest virus (SFV) and murine hepatitis virus (MHV). The CH24H metabolite, 24-hydroxycholesterol (24HC), also shows competence in inhibiting the replication of multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 24HC can increase the cholesterol concentration in multivesicular body (MVB)/late endosome (LE) by disrupting the interaction between OSBP and VAPA, resulting in viral particles being trapped in MVB/LE, ultimately compromising VSV and RABV entry into host cells. These findings provide the first evidence that brain cholesterol oxidation products may play a critical role in viral infection.

A digital twin-driven flexible scheduling method in a human–machine collaborative workshop based on hierarchical reinforcement learning

Under the influence of the global COVID-19 pandemic, the demand for medical equipment and epidemic prevention materials has increased significantly, but the existing production lines are not flexible and efficient enough to dynamically adapt to market demand. The human–machine collaboration system combines the advantages of humans and machines, and provides feasibility for implementing different manufacturing tasks. With dynamic adjustment of robots and operators in the production line, the flexibility of the human–machine collaborative production line can be further improved. Therefore, a parallel production line is set up as a parallel community, and the digital twin community model of the intelligent workshop is constructed. The fusion and interaction between the production communities enhance the production flexibility of the manufacturing shop. Aiming at the overall production efficiency and load balancing state, a digital twin-driven intra-community process optimization algorithm based on hierarchical reinforcement learning is proposed, and as a key framework to improve the production performance of production communities, which is used to optimize the proportion of human and machine involvement in work. Finally, taking the assembly process of ventilators as an example, it is proved that the intelligent scheduling strategy proposed in this paper shows stronger adjustment ability in response to dynamic demand as well as production line changes.

Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation.

Currently, human health due to corona virus disease 2019 (COVID-19) pandemic has been seriously threatened. The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19. However, the efficacy is compromised by the SARS-CoV-2 evolvement and mutation. Here we report the SARS-CoV-2 S protein receptor-binding domain (RBD) inhibitor licorice-saponin A3 (A3) could widely inhibit RBD of SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, XBB and BQ1.1. Furthermore, A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells, with EC50 of 1.016 µM. The mechanism was related with binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis combined with quantum mechanics/molecular mechanics (QM/MM) simulations. Interestingly, phosphoproteomics analysis and multi fluorescent immunohistochemistry (mIHC) respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 MAPK pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.

Impact of lockdown policies during the COVID-19 outbreak on a trauma center of a tertiary hospital in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a major and costly public health emergency. AIM: To investigate the impact of China's lockdown policies during the COVID-19 outbreak on the level I trauma center of a tertiary comprehensive hospital of Traditional Chinese Medicine. METHODS: All patients admitted to our trauma center during a lockdown in 2020 and the same period in 2019 were enrolled. We collected data on demographics, daily visits, injury type, injury mechanism, injury severity score, and patient management for comparative analysis. RESULTS: The total number of patients in the trauma center of our hospital decreased by 50.38% during the COVID-19 Lockdown in 2020 compared to the same period in 2019. The average number of trauma visits per day in 2019 was 47.94, compared to 23.79 in 2020. Comparing the patients' demographic data, loss of employment was the most predominate characteristic in 2020 compared to 2019, while there was no significant difference in gender, age, and marital status between both periods. During the lockdown period, the proportion of traffic accident-related injuries, injuries due to falls greater than 1.5 m, and mechanical injuries decreased significantly, whereas the proportion of injuries caused by falls less than 1.5 m, cuts, assault, bites, and suicidal tendencies and other injuries increased relatively. In addition, the proportion of patients with minor injuries increased and serious injuries decreased during the lockdown. The hospitalization rate increased significantly, and there was no significant difference in emergency surgery and death rates. CONCLUSION: The lockdown policies during the COVID-19 outbreak significantly altered the number and mechanism of traumatic events in our hospital, which can be monitored regularly. Our results suggest that mandatory public health prevention and control measures by the government can reduce the incidence of traumatic events and the severity of traumatic injuries. Emergency surgery and mortality rates remain high, increased because of factors such as family injury and penetrating injury, and hospitalization rates have increased significantly. Therefore, our trauma center still needs to be fully staffed. Finally, from the perspective of the injury mechanism, indoor trauma is a major risk during a lockdown, and it is particularly important to develop prevention strategies for such trauma to reduce the medical burden of the next catastrophic epidemic.

Developmental changes in and the relationship between psychological resilience and mental health problems in adolescents relocated for poverty alleviation in the context of COVID-19 epidemic prevention and control.

Background: Adolescents relocated for poverty alleviation have considerable mental health problems (MHPs) in the context of changing living environments and COVID-19 epidemic prevention and control, and psychological resilience (PR) is closely related to MHPs. Existing studies have mainly used cross-sectional research to investigate the relationship between PR and MHPs using PR as a predictor variable. Objective: This study investigated developmental changes in the PR and MHPs of relocated adolescents as well as the relationship between these factors. Methods: A longitudinal study was conducted to assess the PR and MHPs of 1,284 relocated adolescents. Data were collected at approximately 12-month intervals at three time points: spring of 2020 (T1), spring of 2021 (T2), and spring of 2022 (T3). The 1284 adolescents consisted of 620 males and 664 females; 787 were in the fourth grade of elementary school, 455 were in the first grade of middle school, and 42 were in the first grade of high school. The collected data were analyzed using SPSS 25.0 and Mplus 8.1 and methods such as latent growth models and cross-lagged regression analysis. Results: (1) The PR level of relocated adolescents showed an overall increasing trend (slope = 0.16, p < 0.01), while the MHPs showed an overall decreasing trend (slope = -0.03, p < 0.01). (2) The initial PR level differed significantly from the initial MHPs level (ß = -0.755, p = 0.00), and the rate of change in PR differed significantly from the rate of change in MHPs (ß = -0.566, p = 0). The initial MHPs level differed significantly from that of PR (ß = -0.732, p = 0.00), and the rate of change in MHPs differed significantly from the rate of change in PR (ß = -0.514, p = 0.00). (3) Among the three sets of measurements of PR and MHPs, there were significant pairwise differences. Conclusion: (1) The PR level of relocated adolescents increased over time, and the MHPs of relocated adolescents decreased over time. (2) The initial PR level of relocated adolescents had a negative predictive effect on the initial MHPs level, and the rate of change in PR had a negative predictive effect on the rate of change in MHPs. (3) The PR and MHPs of relocated adolescents exhibited a bidirectional, mutually influencing relationship.

Cross-species recognition and molecular basis of SARS-CoV-2 and SARS-CoV binding to ACE2s of marine animals.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has an extremely broad host range that includes hippopotami, which are phylogenetically closely related to whales. The cellular ACE2 receptor is one of the key determinants of the host range. Here, we found that ACE2s from several marine mammals and hippopotami could efficiently bind to the receptor-binding domain (RBD) of both SARS-CoV and SARS-CoV-2 and facilitate the transduction of SARS-CoV and SARS-CoV-2 pseudoviruses into ACE2-expressing cells. We further resolved the cryo-electron microscopy complex structures of the minke whale ACE2 and sea lion ACE2, respectively, bound to the RBDs, revealing that they have similar binding modes to human ACE2 when it comes to the SARS-CoV-2 RBD and SARS-CoV RBD. Our results indicate that marine mammals could potentially be new victims or virus carriers of SARS-CoV-2, which deserves further careful investigation and study. It will provide an early warning for the prospective monitoring of marine mammals.

Rapid evaluation of heterologous chimeric RBD-dimer mRNA vaccine for currently-epidemic Omicron sub-variants as booster shot after inactivated vaccine

Graphical With continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines, especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries. Previously, we developed a coronavirus disease 2019 (COVID-19) protein subunit vaccine ZF2001® based on the tandem homo-prototype receptor-binding domain (RBD)-dimer of the SARS-CoV-2 spike protein. We upgraded the antigen into a hetero-chimeric prototype (PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms. Herein, we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine in mice. Our data demonstrated that the chimeric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the variants, and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice, shedding light on the antigen design for the next-generation COVID-19 vaccines.

The impact of COVID-19 pandemic on emotional and behavioral problems of children with autism spectrum disorder and developmental delay aged 1–6 years in China

Introduction The COVID-19 pandemic outbreak have caused increased levels of emotional and behavioral problems, particularly among people with pre-existing mental health conditions. Young individuals with autism spectrum disorders (ASD) and developmental delay (DD) are particularly at risk due to their vulnerability. The purpose of this study was to look into the different effects of the COVID-19 pandemic on 1–6-year-old children with ASD and DD. Methods Parents and guardians of children with ASD completed an online survey that included questions about their children's socio-demographics characteristics, the effects of the COVID-19 outbreak on their health, and what they needed in order to deal with the conditions of the pandemic. Results This study compared 4,138 children with ASD to 711 children with DD. Children with ASD had a higher risk of having more emotional and behavioral problems than children with DD (OR 1.38, 95% CI 1.12–1.70). Compared to parent-oriented rehabilitation at home, discontinuing rehabilitation had a higher likelihood of negative emotional and behavioral change (OR 1.67, 95% CI 1.41–1.98). Having teachers' online support had a higher likelihood of negative emotional and behavioral change for ASD children (OR 1.26, 95% CI 1.03–1.54). Conclusions This article provided evidence that children with developmental disabilities, particularly ASD, were at risk for a variety of challenges to their emotional functioning during the COVID-19 period, and that online support was not an ideal way for children with ASD to receive effective educational intervention in China.

The impact of COVID-19 pandemic on emotional and behavioral problems of children with autism spectrum disorder and developmental delay aged 1-6 years in China.

Introduction: The COVID-19 pandemic outbreak have caused increased levels of emotional and behavioral problems, particularly among people with pre-existing mental health conditions. Young individuals with autism spectrum disorders (ASD) and developmental delay (DD) are particularly at risk due to their vulnerability. The purpose of this study was to look into the different effects of the COVID-19 pandemic on 1-6-year-old children with ASD and DD. Methods: Parents and guardians of children with ASD completed an online survey that included questions about their children's socio-demographics characteristics, the effects of the COVID-19 outbreak on their health, and what they needed in order to deal with the conditions of the pandemic. Results: This study compared 4,138 children with ASD to 711 children with DD. Children with ASD had a higher risk of having more emotional and behavioral problems than children with DD (OR 1.38, 95% CI 1.12-1.70). Compared to parent-oriented rehabilitation at home, discontinuing rehabilitation had a higher likelihood of negative emotional and behavioral change (OR 1.67, 95% CI 1.41-1.98). Having teachers' online support had a higher likelihood of negative emotional and behavioral change for ASD children (OR 1.26, 95% CI 1.03-1.54). Conclusions: This article provided evidence that children with developmental disabilities, particularly ASD, were at risk for a variety of challenges to their emotional functioning during the COVID-19 period, and that online support was not an ideal way for children with ASD to receive effective educational intervention in China.

Rational development of multicomponent mRNA vaccine candidates against mpox.

The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of Orthopoxvirus genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health emergency of international concern since July 2022. Inspired by the unprecedent success of coronavirus disease 2019 (COVID-19) mRNA vaccines, the development of a safe and effective mRNA vaccine against MPXV is of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we rationally constructed and prepared a panel of multicomponent MPXV vaccine candidates encoding different combinations of viral antigens including M1R, E8L, A29L, A35R, and B6R. In vitro and in vivo characterization demonstrated that two immunizations of all mRNA vaccine candidates elicit a robust antibody response as well as antigen-specific Th1-biased cellular response in mice. Importantly, the penta- and tetra-component vaccine candidates AR-MPXV5 and AR-MPXV4a showed superior capability of inducing neutralizing antibodies as well as of protecting from VACV challenge in mice. Our study provides critical insights to understand the protection mechanism of MPXV infection and direct evidence supporting further clinical development of these multicomponent mRNA vaccine candidates.

Efficacy of nasal irrigation and oral rinse with sodium bicarbonate solution on virus clearance for COVID-19 patients.

Background: Recent studies have shown that the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reduced under alkaline conditions. The purpose of this study is to assess the effect of nasal irrigation and oral rinse with sodium bicarbonate solution on virus clearance among COVID-19 patients. Materials and methods: COVID-19 patients were recruited and randomly divided into two group, i.e., the experimental group and the control group. The experimental group received regular care plus nasal irrigation and oral rinse with 5% sodium bicarbonate solution, while the control group only received regular care. Nasopharyngeal and oropharyngeal swab samples were collected daily for reverse transcription-polymerase chain reaction (RT-PCR) assays. The negative conversion time and hospitalization time of the patients were recorded, and the results were statistically analyzed. Results: A total of 55 COVID-19 patients with mild or moderate symptoms were included in our study. There was no significant difference in gender, age and health status between the two groups. The average negative conversion time was 1.63 days after treatment with sodium bicarbonate, and the average hospitalization time of the control group and the experimental group were 12.53 and 7.7 days, respectively. Conclusions: Nasal irrigation and oral rinse with 5% sodium bicarbonate solution is effective in virus clearance for COVID-19 patients.

Evolution of Immune Evasion and Host Range Expansion by the SARS-CoV-2 B.1.1.529 (Omicron) Variant.

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron) has rapidly become the dominant strain, with an unprecedented number of mutations within its spike gene. However, it remains unknown whether these variants have alterations in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies and entry inhibitors. In this study, we found that Omicron spike has evolved to escape neutralization by three-dose inactivated-vaccine-elicited immunity but remains sensitive to an angiotensin-converting enzyme 2 (ACE2) decoy receptor. Moreover, Omicron spike could use human ACE2 with a slightly increased efficiency while gaining a significantly increased binding affinity for a mouse ACE2 ortholog, which exhibits limited binding with wild-type (WT) spike. Furthermore, Omicron could infect wild-type C57BL/6 mice and cause histopathological changes in the lungs. Collectively, our results reveal that evasion of neutralization by vaccine-elicited antibodies and enhanced human and mouse ACE2 receptor engagement may contribute to the expanded host range and rapid spread of the Omicron variant. IMPORTANCE The recently emerged SARS-CoV-2 Omicron variant with numerous mutations in the spike protein has rapidly become the dominant strain, thereby raising concerns about the effectiveness of vaccines. Here, we found that the Omicron variant exhibits a reduced sensitivity to serum neutralizing activity induced by a three-dose inactivated vaccine but remains sensitive to entry inhibitors or an ACE2-Ig decoy receptor. Compared with the ancestor strain isolated in early 2020, the spike protein of Omicron utilizes the human ACE2 receptor with enhanced efficiency while gaining the ability to utilize mouse ACE2 for cell entry. Moreover, Omicron could infect wild-type mice and cause pathological changes in the lungs. These results reveal that antibody evasion, enhanced human ACE2 utilization, and an expanded host range may contribute to its rapid spread.

Rapid evaluation of heterologous chimeric RBD-dimer mRNA vaccine for currently-epidemic Omicron sub-variants as booster shot after inactivated vaccine.

With continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the severe immune escape of Omicron sub-variants urges the development of next-generation broad-spectrum vaccines, especially as booster jabs after high-level vaccination coverage of inactivated vaccines in China and many other countries. Previously, we developed a coronavirus disease 2019 (COVID-19) protein subunit vaccine ZF2001® based on the tandem homo-prototype receptor-binding domain (RBD)-dimer of the SARS-CoV-2 spike protein. We upgraded the antigen into a hetero-chimeric prototype (PT)-Beta or Delta-BA.1 RBD-dimer to broaden the cross-protection efficacy and prove its efficiency with protein subunit and mRNA vaccine platforms. Herein, we further explored the hetero-chimeric RBD-dimer mRNA vaccines and evaluated their broad-spectrum activities as booster jabs following two doses of inactivated vaccine (IV) in mice. Our data demonstrated that the chimeric vaccines significantly boosted neutralizing antibody levels and specific T-cell responses against the variants, and PT-Beta was superior to Delta-BA.1 RBD as a booster in mice, shedding light on the antigen design for the next-generation COVID-19 vaccines.

MXene-Based Aptameric Fluorosensor for Sensitive and Rapid Detection of COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused COVID-19 pandemic has rapidly escalated into the largest global health emergency, which pushes to develop detection kits for the detection of COVID-19 with high sensitivity, specificity, and fast analysis. Here, aptamer-functionalized MXene nanosheet is demonstrated as a novel bionanosensor that detects COVID-19. Upon binding to the spike receptor binding domain of SARS-CoV-2, the aptamer probe is released from MXene surface restoring the quenched fluorescence. The performances of the fluorosensor are evaluated using antigen protein, cultured virus, and swab specimens from COVID-19 patients. It is evidenced that this sensor can detect SARS-CoV-2 spike protein at final concentration of 38.9 fg mL-1 and SARS-CoV-2 pseudovirus (limit of detection: 7.2 copies) within 30 min. Its application for clinical samples analysis is also demonstrated successfully. This work offers an effective sensing platform for sensitive and rapid detection of COVID-19 with high specificity.

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

Characterization and pathogenicity of the porcine epidemic diarrhea virus isolated in China.

Piglet diarrhea caused by the porcine epidemic diarrhea virus (PEDV) is a common problem on pig farms in China associated with high morbidity and mortality rates. In this study, three PEDV isolates were successfully detected after the fourth blind passage in Vero cells. The samples were obtained from infected piglet farms in Jilin (Changchun), and Shandong (Qingdao) Provinces of China and were designated as CH/CC-1/2018, CH/CC-2/2018, and CH/QD/2018. According to the analysis of the complete S protein gene sequence, the CH/CC-1/2018 and CH/CC-2/2018 were allocated to the G2b branch, while CH/QD/2018 was located in the G1a interval and was closer to the vaccine strain CV777. Successful detection and identification of the isolated strains were carried out using electron microscopy and indirect immunofluorescence. Meanwhile, animal challenge experiments and viral RNA copies determination were used to compare the pathogenicity. The results showed that CH/CC-1/2018 in Changchun was more pathogenic than CH/QD/2018 in Qingdao. In conclusion, the discovery of these new strains is conducive to the development of vaccines to prevent the pandemic of PEDV, especially that the CH/CC-1/2018, and CH/CC-2/2018 were not related to the classical vaccine strain CV777.

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. A novel oral noncovalent inhibitor of 3C-like protease, named WU-04, was developed as a promising drug candidate for COVID-19 treatment.