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1.
Signal Transduct Target Ther ; 6(1): 167, 2021 04 24.
Article in English | MEDLINE | ID: covidwho-1203416

ABSTRACT

The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid-liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.


Subject(s)
/metabolism , NF-kappa B/metabolism , RNA, Viral/metabolism , Signal Transduction , A549 Cells , Acrylates/pharmacology , Animals , /pathology , Chlorocebus aethiops , HEK293 Cells , HeLa Cells , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Phosphoproteins/metabolism , Vero Cells
2.
Eur J Integr Med ; : 101323, 2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1126825

ABSTRACT

Introduction: Early in the epidemic of corona virus disease 2019, the Chinese government recruited a proportion of healthcare workers to support the designated hospital (Huoshenshan Hospital) in Wuhan, China. The majority of front-line medical staff suffered from adverse effects, but their real health status during COVID-19 epidemic was still unknown. The aim of the study was to explore the latent relationship of the physical and mental health of front-line medical staff during this special period. Methods: A total of 115 military medical staff were recruited between February 17th and February 29th, 2020 and asked to complete questionnaires assessing socio-demographic and clinical characteristics, self-reported sleep status, fatigue, resilience and anxiety. Results: 55 medical staff worked within Intensive Care and 60 worked in Non-intensive Care, the two groups were significantly different in general fatigue, physical fatigue and tenacity (P<0.05). Gender, duration working in Wuhan, current perceived stress level and health status had significant differences in fatigue scores (P<0.05), the current perceived health status (P<0.05) impacted on the resilience and anxiety of participants. The structural equation modeling analysis revealed resilience were negatively associated with fatigue (ß=-0.52, P<0.01) and anxiety (ß=-0.24, P<0.01), and fatigue had direct association with the physical burden (ß=0.65, P<0.01); Fatigue mediated the relationship between resilience and anxiety (ß=-0.305, P=0.039) as well as resilience and physical burden (ß=-0.276, P=0.02). Conclusion: During an explosive pandemic, motivating the effect of protective resilience and taking tailored interventions against fatigue are promising ways to protect the physical and mental health of the front-line medical staff.

3.
Proc Natl Acad Sci U S A ; 117(44): 27381-27387, 2020 11 03.
Article in English | MEDLINE | ID: covidwho-867659

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Drug Repositioning , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Cysteine Endopeptidases , Dipyridamole/pharmacology , Humans , Hydroxychloroquine/pharmacology , Molecular Docking Simulation , Molecular Structure , Pandemics , Pneumonia, Viral/drug therapy
4.
Acta Pharm Sin B ; 10(7): 1205-1215, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-88716

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

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