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1.
J Med Chem ; 65(4): 2940-2955, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1475245

ABSTRACT

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Binding Sites/drug effects , COVID-19/metabolism , Coronavirus Papain-Like Proteases/isolation & purification , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Pandemics , Surface Plasmon Resonance , Tumor Cells, Cultured
2.
JMIR Med Inform ; 8(9): e19588, 2020 Sep 08.
Article in English | MEDLINE | ID: covidwho-993019

ABSTRACT

BACKGROUND: In late December 2019, a pneumonia caused by SARS-CoV-2 was first reported in Wuhan and spread worldwide rapidly. Currently, no specific medicine is available to treat infection with COVID-19. OBJECTIVE: The aims of this study were to summarize the epidemiological and clinical characteristics of 175 patients with SARS-CoV-2 infection who were hospitalized in Renmin Hospital of Wuhan University from January 1 to January 31, 2020, and to establish a tool to identify potential critical patients with COVID-19 and help clinical physicians prevent progression of this disease. METHODS: In this retrospective study, clinical characteristics of 175 confirmed COVID-19 cases were collected and analyzed. Univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were used to select variables. Multivariate analysis was applied to identify independent risk factors in COVID-19 progression. We established a nomogram to evaluate the probability of progression of the condition of a patient with COVID-19 to severe within three weeks of disease onset. The nomogram was verified using calibration curves and receiver operating characteristic curves. RESULTS: A total of 18 variables were considered to be risk factors after the univariate regression analysis of the laboratory parameters (P<.05), and LASSO regression analysis screened out 10 risk factors for further study. The six independent risk factors revealed by multivariate Cox regression were age (OR 1.035, 95% CI 1.017-1.054; P<.001), CK level (OR 1.002, 95% CI 1.0003-1.0039; P=.02), CD4 count (OR 0.995, 95% CI 0.992-0.998; P=.002), CD8 % (OR 1.007, 95% CI 1.004-1.012, P<.001), CD8 count (OR 0.881, 95% CI 0.835-0.931; P<.001), and C3 count (OR 6.93, 95% CI 1.945-24.691; P=.003). The areas under the curve of the prediction model for 0.5-week, 1-week, 2-week and 3-week nonsevere probability were 0.721, 0.742, 0.87, and 0.832, respectively. The calibration curves showed that the model had good prediction ability within three weeks of disease onset. CONCLUSIONS: This study presents a predictive nomogram of critical patients with COVID-19 based on LASSO and Cox regression analysis. Clinical use of the nomogram may enable timely detection of potential critical patients with COVID-19 and instruct clinicians to administer early intervention to these patients to prevent the disease from worsening.

4.
Aging (Albany NY) ; 12(20): 19898-19910, 2020 10 26.
Article in English | MEDLINE | ID: covidwho-892548

ABSTRACT

The number of corona virus disease 2019 cases is increasing rapidly. However, the comparison of clinical characteristics between patients ≥ 70 and those < 70 has not been implemented yet. To achieve that, we collected clinical data of consecutive 222 patients in Renmin Hospital of Wuhan University diagnosed between January 13, 2020 and February 4, 2020. We divided them into an under-70 group and an over-70 group according to their ages, comparing their clinical characteristics. Meanwhile, univariate and multivariate Cox regression analyses were performed to identify the prognostic factors. Among the patients enrolled, 37 (16.67%) were 70 or older and 185 (83.33%) were younger than 70. Higher proportions of dyspnoea, expectoration, chronic cardiovascular disease, diabetes, organ complications, severe-to-critical cases, a higher death rate, a longer hospital stay and decreased immune status were observed in the over-70 group patients compared with their younger counterparts. The risk factors for death included dyspnoea, muscle ache, elevated myocardial enzymes, elevated C3 in over-70 patients and dyspnoea, pharyngalgia, chronic cardiac disease, increased C-reactive protein, IgA, decreased platelets in under-70 patients. Overall, our research compared the clinical characteristics of the two populations with different immune status and illustrated differentiated risk factors for death in them.


Subject(s)
Coronavirus Infections/mortality , Pneumonia, Viral/mortality , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19 , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Prognosis , Young Adult
6.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-701

ABSTRACT

Background: In late December 2019, a pneumonia caused by SARS-CoV-2 was first discovered in Wuhan, and it spread worldwide. Until now, no specific medicine has

8.
Protein Cell ; 11(10): 723-739, 2020 10.
Article in English | MEDLINE | ID: covidwho-697126

ABSTRACT

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Oxidoreductases/antagonists & inhibitors , Pandemics , Pneumonia, Viral/drug therapy , RNA Viruses/drug effects , Thiazoles/pharmacology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/physiology , Binding Sites/drug effects , COVID-19 , Cell Line , Coronavirus Infections/virology , Crotonates/pharmacology , Cytokine Release Syndrome/drug therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Humans , Hydroxybutyrates , Influenza A virus/drug effects , Leflunomide/pharmacology , Mice , Mice, Inbred BALB C , Nitriles , Orthomyxoviridae Infections/drug therapy , Oseltamivir/therapeutic use , Oxidoreductases/metabolism , Oxidoreductases Acting on CH-CH Group Donors , Pneumonia, Viral/virology , Protein Binding/drug effects , Pyrimidines/biosynthesis , RNA Viruses/physiology , SARS-CoV-2 , Structure-Activity Relationship , Thiazoles/therapeutic use , Toluidines/pharmacology , Ubiquinone/metabolism , Virus Replication/drug effects
9.
Cell Host Microbe ; 28(1): 124-133.e4, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-378130

ABSTRACT

Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections , Disease Models, Animal , Mice, Inbred C57BL , Pandemics , Pneumonia, Viral , Aging , Angiotensin-Converting Enzyme 2 , Animals , Brain/virology , COVID-19 , CRISPR-Cas Systems , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/blood , Gene Knock-In Techniques , Lung/pathology , Lung/virology , Lung Diseases, Interstitial/pathology , Nose/virology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA, Viral/analysis , SARS-CoV-2 , Stomach/virology , Trachea/virology , Viral Load , Virus Replication
10.
J Clin Virol ; 127: 104361, 2020 06.
Article in English | MEDLINE | ID: covidwho-47186

ABSTRACT

OBJECTIVES: To explore the clinical course and its dynamic features of immune status in COVID-19 patients and find predictors correlated with severity and prognosis of COVID-19. METHODS: The electronic medical records of 204 patients with COVID-19 pneumonia confirmed by nucleic acid testing were retrospectively collected and analyzed. RESULTS: All patients were divided into severe (69) and non-severe group (135). Lymphocyte subsets count, including CD3+ T cell, CD4+ T cell, CD8+ T cell, B cell (CD19+) and NK cell (CD16+ 56+), were significantly lower in severe group (P<0.001). The dynamic levels of T lymphocyte in severe group were significantly lower from disease onset, but in the improved subgroup the value of T lymphocyte began to increase after about 15-day treatment and finally returned to the normal level. The cut-off value of the counts of CD3+ (576), CD4+ (391) and CD8+ (214) T cell were calculated and indicated significantly high sensitivity and specificity for severity of COVID-19. CONCLUSION: Our results shown that the decrease of CD3+, CD4+ and CD8+ T lymphocyte correlated with the course of patients with COVID-19 pneumonia, especially in severe cases. The level of T lymphocyte could be used as an indicator for prediction of severity and prognosis of patients with COVID-19 pneumonia. The application of glucocorticoid should be cautious in severe cases.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/immunology , Lymphocyte Subsets/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Adult , Aged , Betacoronavirus , COVID-19 , Electronic Health Records , Female , Humans , Lymphocyte Count , Male , Middle Aged , Pandemics , Prognosis , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology
11.
J Infect ; 81(1): e33-e39, 2020 07.
Article in English | MEDLINE | ID: covidwho-46567

ABSTRACT

PURPOSE: Aimed to characterize the CT imaging and clinical course of asymptomatic cases with COVID-19 pneumonia. METHODS: Asymptomatic cases with COVID-19 pneumonia confirmed by SARS-COV-2 nucleic acid testing in Renmin Hospital of Wuhan University were retrospectively enrolled. The characteristics of CT imaging and clinical feature were collected and analyzed. RESULTS: 58 asymptomatic cases with COVID-19 pneumonia admitted to our hospital between Jan 1, 2020 and Feb 23, 2020 were enrolled. All patients had history of exposure to SARS-CoV-2. On admission, patients had no symptoms and laboratory findings were normal. The predominant feature of CT findings in this cohort was ground glass opacity (GGO) (55, 94.8%) with peripheral (44, 75.9%) distribution, unilateral location (34, 58.6%) and mostly involving one or two lobes (38, 65.5%), often accompanied by characteristic signs. After short-term follow-up, 16 patients (27.6%) presented symptoms with lower lymphocyte count and higher CRP, mainly including fever, cough and fatigue. The evolution of lesions on CT imaging were observed in 10 patients (17.2%). The average days of hospitalization was19.80±10.82 days, and was significantly longer in progression patients (28.60±7.55 day). CONCLUSION: CT imaging of asymptomatic cases with COVID-19 pneumonia has definite characteristics. Since asymptomatic infections as "covert transmitter", and some patients can progress rapidly in the short term. It is essential to pay attention to the surveillance of asymptomatic patients with COVID-19. CT scan has great value in screening and detecting patients with COVID-19 pneumonia, especially in the highly suspicious, asymptomatic cases with negative nucleic acid testing.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/pathology , Lung/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/pathology , Adult , Betacoronavirus/genetics , COVID-19 , China , Cohort Studies , Female , Humans , Lung/pathology , Male , Middle Aged , Pandemics , Retrospective Studies , SARS-CoV-2 , Tomography, X-Ray Computed
12.
Chinese Journal of Pediatrics ; - (12):5-5, 2020.
Article | WHO COVID | ID: covidwho-7618

ABSTRACT

Summary One patient with a complaint of "intermittent diarrhea, vomiting for 6 days, fever with shortness of breath for half a day" was referred to the Department of Critical Medicine, Wuhan Children's Hospital, and was diagnosed with neonatal severe coronavirus pneumonia (NCP). Relevant databases such as China Knowledge Net, Weipu, Wanfang and other related databases were searched with the keywords of "new coronavirus pneumonia", "children", and "critical severity" as of February 8, 2020. This case is the first child with severe NCP in China. It started with gastrointestinal symptoms, early respiratory symptoms were not obvious, and rapidly progressed to acute respiratory distress syndrome, septic shock, and acute renal failure. The patient was negative for nucleic acid test of 2019 new-type coronavirus (2019-nCoV) for 2 consecutive consecutive throat swabs. For severe suspected cases, it is recommended to take samples of the lower respiratory tract or repeat samples of the upper respiratory tract for testing. Continuous blood purification technology can be applied to the treatment of children with severe NCP as early as possible.

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