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1.
European journal of medicinal chemistry ; 2022.
Article in English | EuropePMC | ID: covidwho-1876900

ABSTRACT

The COVID-19 posed a serious threat to human life and health, and SARS-CoV-2 Mpro has been considered as an attractive drug target for the treatment of COVID-19. Herein, we report 2-(furan-2-ylmethylene)hydrazine-1-carbothioamide derivatives as novel inhibitors of SARS-CoV-2 Mpro developed by in-house library screening and biological evaluation. Similarity search led to the identification of compound F8–S43 with the enzymatic IC50 value of 10.76 μM. Further structure-based drug design and synthetic optimization uncovered compounds F8–B6 and F8–B22 as novel non-peptidomimetic inhibitors of Mpro with IC50 values of 1.57 μM and 1.55 μM, respectively. Moreover, enzymatic kinetic assay and mass spectrometry demonstrated that F8–B6 was a reversible covalent inhibitor of Mpro. Besides, F8–B6 showed low cytotoxicity with CC50 values of more than 100 μM in Vero and MDCK cells. Overall, these novel SARS-CoV-2 Mpro non-peptidomimetic inhibitors provide a useful starting point for further structural optimization. Graphical Image 1

2.
J Med Virol ; 94(7): 3240-3250, 2022 07.
Article in English | MEDLINE | ID: covidwho-1850119

ABSTRACT

To observe the predictive effect of fasting blood glucose (FBG) level on the prognosis, clinical sequelae, and pulmonary absorption in hospitalized coronavirus disease 2019 (COVID-19) patients with and without a history of diabetes, respectively, and to evaluate the correlation between the dynamic changes of FBG and poor prognosis. In this bidirectional cohort study, we enrolled 2545 hospitalized COVID-19 patients (439 diabetics and 2106 without a diabetic history) and followed up for 1 year. The patients were divided according to the level of admission FBG. The dynamic changes of FBG were compared between the survival and the death cases. The prediction effect of FBG on 1-year mortality and sequelae was analyzed. The 1-year all cause mortality rate and in-hospital mortality rate of COVID-19 patients were J-curve correlated with FBG (p < 0.001 for both in the nondiabetic history group, p = 0.004 and p = 0.01 in the diabetic history group). FBG ≥ 7.0 mmol/L had a higher risk of developing sequelae (p = 0.025) and have slower recovery of abnormal lung scans (p < 0.001) in patients who denied a history of diabetes. Multivariable Cox regression analysis showed that FBG ≥ 7.0 mmol/L was an independent risk factor for the mortality of COVID-19 regardless of the presence or deny a history of diabetes (hazard atio [HR] = 10.63, 95% confidence interval [CI]: 7.15-15.83, p < 0.001; HR = 3.9, 95% CI: 1.56-9.77, p = 0.004, respectively). Our study shows that FBG ≥ 7.0 mmol/L can be a predictive factor of 1-year all-cause mortality in COVID-19 patients, independent of diabetes history. FBG ≥ 7.0 mmol/L has an advantage in predicting the severity, clinical sequelae, and pulmonary absorption in COVID-19 patients without a history of diabetes. Early detection, timely treatment, and strict control of blood glucose when finding hyperglycemia in COVID-19 patients (with or without diabetes) are critical for their prognosis.


Subject(s)
COVID-19 , Diabetes Mellitus , Blood Glucose/analysis , COVID-19/complications , Cohort Studies , Disease Progression , Fasting , Humans , Prognosis , Retrospective Studies , Risk Factors
3.
Am J Clin Nutr ; 115(4): 1123-1133, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1774329

ABSTRACT

BACKGROUND: Vitamin D may have a role in immune responses to viral infections. However, data on the association between vitamin D and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) severity have been limited and inconsistent. OBJECTIVE: We examined the associations of predicted vitamin D status and intake with risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: We used data from periodic surveys (May 2020 to March 2021) within the Nurses' Health Study II. Among 39,315 participants, 1768 reported a positive test for SARS-CoV-2 infection. Usual vitamin D intake from foods and supplements were measured using a semiquantitative, pre-pandemic food-frequency questionnaire in 2015. Predicted 25-hydroxyvitamin D [25(OH)D] concentration were calculated based on a previously validated model including dietary and supplementary vitamin D intake, UV-B, and other behavioral predictors of vitamin D status. RESULTS: Higher predicted 25(OH)D concentrations, but not vitamin D intake, were associated with a lower risk of SARS-CoV-2 infection. Comparing participants in the highest quintile of predicted 25(OH)D concentrations with the lowest, the multivariable-adjusted OR was 0.76 (95% CI: 0.58, 0.99; P-trend = 0.04). Participants in the highest quartile of UV-B (OR: 0.76; 95% CI: 0.66, 0.87; P-trend = 0.002) and UV-A (OR: 0.76; 95% CI: 0.66, 0.88; P-trend < 0.001) also had a lower risk of SARS-CoV-2 infection compared with the lowest. High intake of vitamin D from supplements (≥400 IU/d) was associated with a lower risk of hospitalization (OR: 0.51; 95% CI: 0.29, 0.91; P-trend = 0.04). CONCLUSIONS: Our study provides suggestive evidence on the association between higher predicted circulating 25(OH)D concentrations and a lower risk of SARS-CoV-2 infection. Greater intake of vitamin D supplements was associated with a lower risk of hospitalization. Our data also support an association between exposure to UV-B or UV-A, independently of vitamin D and SARS-CoV-2 infection, so results for predicted 25(OH)D need to be interpreted cautiously.


Subject(s)
COVID-19 , Vitamin D Deficiency , Humans , SARS-CoV-2 , Vitamin D , Vitamins
4.
Cardiovasc Toxicol ; 22(4): 311-325, 2022 04.
Article in English | MEDLINE | ID: covidwho-1773006

ABSTRACT

Hypertension is one of the most prevalent cardiovascular disorders worldwide, affecting 1.13 billion people, or 14% of the global population. Hypertension is the single biggest risk factor for cerebrovascular dysfunction. According to the American Heart Association, high blood pressure (BP), especially in middle-aged individuals (~ 40 to 60 years old), is associated with an increased risk of dementia, later in life. Alzheimer's disease and cerebrovascular disease are the two leading causes of dementia, accounting for around 80% of the total cases and usually combining mixed pathologies from both. Little is known regarding how hypertension affects cognitive function, so the impact of its treatment on cognitive impairment has been difficult to assess. The brain renin-angiotensin system (RAS) is essential for BP regulation and overactivity of this system has been established to precede the development and maintenance of hypertension. Angiotensin II (Ang-II), the main peptide within this system, induces vasoconstriction and impairs neuro-vascular coupling by acting on brain Ang-II type 1 receptors (AT1R). In this review, we systemically analyzed the association between RAS and biological mechanisms of cognitive impairment, from the perspective of AT1R located in the central nervous system. Additionally, the possible contribution of brain AT1R to global cognition decline in COVID-19 cases will be discussed as well.


Subject(s)
COVID-19 , Cognitive Dysfunction , Hypertension , Adult , Angiotensin II/metabolism , Blood Pressure/physiology , COVID-19/complications , Cognitive Dysfunction/diagnosis , Humans , Hypertension/diagnosis , Middle Aged , Receptor, Angiotensin, Type 1/metabolism , Renin-Angiotensin System
5.
Mathematical Problems in Engineering ; 2021, 2021.
Article in English | ProQuest Central | ID: covidwho-1528595

ABSTRACT

Logistics distribution is the terminal link that connects the manufacturer and product user and determines the efficiency of the manufacturer’s service. Therefore, the disruption risk of the joint system is an essential factor affecting the product user experience. In this paper, while considering the product user’s supply disruption risk preference (PUSDRP), a biobjective integer nonlinear programming (INLP) model with subjective cost-utility is proposed to solve the manufacturer’s combined location routing inventory problem (CLRIP). According to the user’s time satisfaction requirement, a routing change selection framework (RCSF) is designed based on the bounded rational behavior of the user. Additionally, the Lagrange Relaxation and Modified Genetic Algorithm (LR-MGA) is proposed. The LR method relaxes the model, and the MGA finds a compromise solution. The experimental results show that the biobjective cost-utility model proposed in this paper is effective and efficient. The RCSF based on user behavior is superior to the traditional expected utility theory model. The compromise solution provides a better solution for the manufacturer order allocation delivery combinatorial optimization problem. The compromise solution not only reduces the manufacturer’s total operating cost but also improves the user's subjective utility. To improve the stability of cooperation between manufacturers and users, the behavior decision-making method urges manufacturers to consider product users’ supply disruption risk preferences (PUSDRPs) in attempting to optimize economic benefits for the long term. This paper uses behavior decision-making methods to expand the ideas of the CLRIP joint system.

7.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1254439

ABSTRACT

The COVID-19 pandemic calls for rapid development of effective treatments. Although various drug repurpose approaches have been used to screen the FDA-approved drugs and drug candidates in clinical phases against SARS-CoV-2, the coronavirus that causes this disease, no magic bullets have been found until now. In this study, we used directed message passing neural network to first build a broad-spectrum anti-beta-coronavirus compound prediction model, which gave satisfactory predictions on newly reported active compounds against SARS-CoV-2. Then, we applied transfer learning to fine-tune the model with the recently reported anti-SARS-CoV-2 compounds and derived a SARS-CoV-2 specific prediction model COVIDVS-3. We used COVIDVS-3 to screen a large compound library with 4.9 million drug-like molecules from ZINC15 database and recommended a list of potential anti-SARS-CoV-2 compounds for further experimental testing. As a proof-of-concept, we experimentally tested seven high-scored compounds that also demonstrated good binding strength in docking studies against the 3C-like protease of SARS-CoV-2 and found one novel compound that can inhibit the enzyme. Our model is highly efficient and can be used to screen large compound databases with millions or more compounds to accelerate the drug discovery process for the treatment of COVID-19.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2/drug effects , Antiviral Agents/therapeutic use , COVID-19/virology , Deep Learning , Humans , Molecular Docking Simulation , Pandemics , SARS-CoV-2/chemistry
8.
World J Clin Cases ; 9(8): 1953-1967, 2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1145712

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is a worldwide pandemic. Some COVID-19 patients develop severe acute respiratory distress syndrome and progress to respiratory failure. In such cases, extracorporeal membrane oxygenation (ECMO) treatment is a necessary life-saving procedure. CASE SUMMARY: Two special COVID-19 cases-one full-term pregnant woman and one elderly (72-year-old) man-were treated by veno-venous (VV)-ECMO in the Second People's Hospital of Zhongshan, Zhongshan City, Guangdong Province, China. Both patients had developed refractory hypoxemia shortly after hospital admission, despite conventional support, and were therefore managed by VV-ECMO. Although both experienced multiple ECMO-related complications on top of the COVID-19 disease, their conditions improved gradually. Both patients were weaned successfully from the ECMO therapy. At the time of writing of this report, the woman has recovered completely and been discharged from hospital to home; the man remains on mechanical ventilation, due to respiratory muscle weakness and suspected lung fibrosis. As ECMO itself is associated with various complications, it is very important to understand and treat these complications to achieve optimal outcome. CONCLUSION: VV-ECMO can provide sufficient gas exchange for COVID-19 patients with acute respiratory distress syndrome. However, it is crucial to understand and treat ECMO-related complications.

9.
J Aerosol Med Pulm Drug Deliv ; 34(2): 108-114, 2021 04.
Article in English | MEDLINE | ID: covidwho-1127303

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 infection is associated with strong infectiousness and has no effective therapy. We aimed to explore the efficacy and safety of Mycobacterium vaccae nebulization in the treatment of Coronavirus Disease 2019 (COVID-19). Methods: In this randomized, double-blind, placebo-controlled clinical trial, we included 31 adult patients with moderate COVID-19 who were admitted to the Fourth People's Hospital of Nanning (Nanning, China) between January 22, 2020 and February 17, 2020. Patients were randomly divided into two groups: group A (standard care group) and group B (M. vaccae in combination with standard care group). The primary outcome was the time interval from admission to viral RNA negative conversion (oropharyngeal swabs were used in this study). Secondary outcomes included chest computed tomography (CT), mortality, length of hospital stay, complications during treatment, and so on. Patients were followed up to 4 weeks after discharge (reexamination of viral RNA, chest CT, etc.). Results: Nucleic acid test negative conversion time in group B was shorter than that in group A (2.9 days [2.7-8.7] vs. 6.8 days [3.3-13.8]; p = 0.045). No death and no conversion to severe or critical cases were observed in both groups. Two weeks after discharge, neither "relapse" nor "return to positive" cases were found. Four weeks after discharge, it was found that there was no case of " relapse " or "return to positive" in group B, and 1 patient in group A showed "return to positive", but there was no clinical manifestation and imaging progression. No adverse reactions related to M. vaccae were found during observation period. Conclusion: M. vaccae treatment might shorten the time interval from admission to viral RNA negative conversion, which might be beneficial to the prevention and treatment of COVID-19. Clinical Trial Registration: ChiCTR2000030016.


Subject(s)
COVID-19/therapy , Length of Stay , Mycobacteriaceae/immunology , Tomography, X-Ray Computed , Administration, Inhalation , Adolescent , Adult , Aged , COVID-19/immunology , COVID-19/mortality , Double-Blind Method , Female , Humans , Male , Middle Aged , Time Factors , Treatment Outcome , Young Adult
10.
J Enzyme Inhib Med Chem ; 36(1): 497-503, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1045926

ABSTRACT

COVID-19 has become a global pandemic and there is an urgent call for developing drugs against the virus (SARS-CoV-2). The 3C-like protease (3CLpro) of SARS-CoV-2 is a preferred target for broad spectrum anti-coronavirus drug discovery. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredients. We found that the ethanol extract of S. baicalensis and its major component, baicalein, inhibit SARS-CoV-2 3CLpro activity in vitro with IC50's of 8.52 µg/ml and 0.39 µM, respectively. Both of them inhibit the replication of SARS-CoV-2 in Vero cells with EC50's of 0.74 µg/ml and 2.9 µM, respectively. While baicalein is mainly active at the viral post-entry stage, the ethanol extract also inhibits viral entry. We further identified four baicalein analogues from other herbs that inhibit SARS-CoV-2 3CLpro activity at µM concentration. All the active compounds and the S. baicalensis extract also inhibit the SARS-CoV 3CLpro, demonstrating their potential as broad-spectrum anti-coronavirus drugs.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Flavanones/pharmacology , Plant Extracts/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , COVID-19/enzymology , COVID-19/virology , Chlorocebus aethiops , Drug Discovery , Enzyme Inhibitors/pharmacology , Humans , In Vitro Techniques , Models, Molecular , SARS-CoV-2/enzymology , Scutellaria baicalensis , Vero Cells
11.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-4483

ABSTRACT

Objective Based on the systematic pharmacol. database of traditional Chinese medicine (TCM) and the anal. platform TCMSP, the computer virtual screening technique was used to find the small mol. inhibitors of TCM for SARS-CoV-2 3CL hydrolase, and to speculate the potential anti-COVID-19 novel coronavirus pneumonia TCMs and traditional Chinese Herbal Compounds Methods SARS-CoV-2 3CL hydrolase protein was targeted in this study. Autodock Vina software and Python script were used to realize high-throughput mol. docking. Combined with "ADME-Lipinski" rules, the re-screening was carried out to optimize the active ingredients and to speculate the key TCMs and compound prescriptions. Based on the perspective of network pharmacol., a component-target-pathway network was constructed to infer the mechanism of action of core drug pairs. Results Taking lopinavir/ritonavir compound preparation as pos. control, 66 natural micromol. compounds with good pharmacokinetic properties were screened out, so that 66 natural micromol. inhibitors with good pharmacokinetic properties were obtained. Eleven single TCMs, two Chinese medicine pairs of Licorice-Mori Cortex and Lonicerae Japonicae Flos-Forsythiae Fructus, and twelve TCM prescriptions including Sangju Drink and Modified Sangju Drink and Yinqiao Powder were selected as candidate schemes to fight against novel coronavirus pneumonia. Conclusion This study is based on high-throughput mol. docking technol. to virtually screen small mol. inhibitors of SARS-CoV-2 3CL hydrolase of TCM and Chinese herbal medicines, innovatively analyze the potential mol. mechanism in combination with network pharmacol., and provide scientific guidance and theor. basis for TCM to resist novel coronavirus pneumonia.

12.
Med Educ ; 55(3): 293-308, 2021 03.
Article in English | MEDLINE | ID: covidwho-742135

ABSTRACT

CONTEXT: Synchronous distance education (SDE) has been widely used for health science students in recent years. This study examined the effectiveness and acceptance of SDE compared with traditional education for health science students and explored the potential moderators that could impact the pooled results. METHODS: A systematic review and meta-analysis was conducted of randomised controlled trials (RCTs) from January 2000 to March 2020 searched on nine electronic databases, including Web of Science, PubMed, Cochrane Library, Scopus, EMBASE, CINAHL, ERIC, PsycINFO, and ProQuest Dissertations and Theses. The outcomes measured were knowledge, skills with objective assessments and overall satisfaction with subjective evaluations. The pooled results were calculated using random-model effects, and moderators were explored through meta-regression. RESULTS: A total of seven RCTs with 594 participants were included. At the post-test level, the pooled effect size of knowledge acquisitions (SMD 0.12, 95% CI -0.07-0.32) showed insignificant difference between the SDE and traditional education groups (P = .207), with low heterogeneity (I2  = 17.6%). Subgroup analyses observed no factors that significantly impacted the pooled results of knowledge acquisition at the post-test levels (P for interaction > 0.05). Knowledge gains from pretest to post-test in SDE groups also did not differ significantly between groups (SMD 0.15, 95% CI -0.22-0.53; P = .428). The pooled effect size of skills (SMD 0.02, 95% CI -0.24-0.28; P = .735) was similarly insignificant. The pooled effect size of overall satisfaction (SMD 0.60, 95% CI 0.38-0.83; P < .001) significantly favoured SDE over traditional education. Incorporating two-group studies without randomisations did not significantly change the overall results of knowledge acquisition at the post-test level (SMD -0.002, 95% CI -0.11-0.10; P = .994), with moderate heterogeneity (I2  = 61.9%). CONCLUSIONS: Synchronous distance education was not significantly different from traditional education in effectiveness and had higher satisfaction ratings. Our findings might provide indications for adoptions of online remote education in health science education centres.


Subject(s)
Education, Distance , Education, Medical , Randomized Controlled Trials as Topic , Students, Health Occupations , COVID-19 , Humans
13.
Eur J Med Chem ; 206: 112702, 2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-724946

ABSTRACT

SARS-CoV-2 3C-like protease is the main protease of SARS-CoV-2 and has been considered as one of the key targets for drug discovery against COVID-19. We identified several N-substituted isatin compounds as potent SARS-CoV-2 3C-like protease inhibitors. The three most potent compounds inhibit SARS-CoV-2 3C-like protease with IC50's of 45 nM, 47 nM and 53 nM, respectively. Our study indicates that N-substituted isatin compounds have the potential to be developed as broad-spectrum anti-coronavirus drugs.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Isatin/therapeutic use , Protease Inhibitors/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/pharmacology , Coronavirus 3C Proteases , Cysteine Endopeptidases , Humans , Isatin/analogs & derivatives , Isatin/chemical synthesis , Models, Molecular , Molecular Docking Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , SARS-CoV-2 , Structure-Activity Relationship
14.
Chin. Trad. Herbal Drugs ; 6(51): 1397-1405, 20200328.
Article in Chinese | WHO COVID, ELSEVIER | ID: covidwho-378401

ABSTRACT

Objective: Based on the systematic pharmacological database of traditional Chinese medicine (TCM) and the analysis platform TCMSP, the computer virtual screening technique was used to screen the small molecule inhibitors of SARS-CoV-2 3CL hydrolase from Chinese materia medica (CMM), and speculate the potential anti-COVID-19 novel coronavirus pneumonia TCMs and its compounds. Methods: SARS-CoV-2 3CL hydrolase protein was targeted in this study. Autodock Vina software and Python script were used to realize high-throughput molecular docking. Combined with “ADME-Lipinski” rules, the re-screening was carried out to optimize the active ingredients and speculate the key TCMs and compound prescriptions. Based on the perspective of network pharmacology, a component-target-pathway network was constructed to infer the mechanism of action of core drug pairs. Results: Taking the reference ligand as positive control, 66 natural micromolecule compounds with good pharmacokinetic properties were obtained. Twelve single TCMs, two Chinese medicine pairs of Glycyrrhizae Radix et Rhizoma-Mori Cortex and Lonicerae Japonicae Flos-Forsythiae Fructus, and 12 TCM prescriptions including Sangju Drink and modified Sangju Drink and Yinqiao Powder were selected as candidate schemes to fight against novel coronavirus pneumonia. Conclusion: This study is based on high-throughput molecular docking technology to virtually screen small molecule inhibitors of SARS-CoV-2 3CL hydrolase of CMM and Chinese medicines, innovatively analyze the potential molecular mechanism in combination with network pharmacology, and provide scientific guidance and theoretical basis for TCM to resist novel coronavirus pneumonia.

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