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OBJECTIVE AND DESIGN: Circulating enzymatic activity and RAAS regulation in severe cases of COVID-19 remains unclear, therefore we measured the serum activity of several proteases as potential targets to control the SARS-CoV-2 infection. MATERIAL OR SUBJECTS: 152 patients with COVID-19-like symptoms were grouped according to the severity of symptoms (COVID-19 negative, mild, moderate and severe). METHODS: Serum samples of COVID-19 patients and controls were subjected to biochemical analysis and enzymatic assays of ACE2, ACE, DPPIV, PREP and CAT L. One-way ANOVA and multivariate logistic regression analysis were used. Statistical significance was accepted at p < 0.05. RESULTS: We detected a positive correlation among comorbidities, higher C-reactive protein (CRP) and D-dimer levels with disease severity. Enzymatic assays revealed an increase in serum ACE2 and CAT L activities in severe COVID-19 patients, while ACE, DPPIV and PREP activities were significantly reduced. Notably, analysis of ACE2/ACE activity ratio suggests a possible imbalance of ANG II/ANG(1-7) ratio, in a positive association with the disease severity. CONCLUSION: Our findings reveal a correlation between proteases activity and the severity of COVID-19. These enzymes together contribute to the activation of pro-inflammatory pathways, trigger a systemic activation of inflammatory mediators, leading to a RAAS dysregulation and generating a significant damage in several organs, contributing to poor outcomes of severe cases.
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COVID-19 , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/enzimología , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Introduction: The enzyme lactate dehydrogenase (LDH) is a good marker of general hyperinflammation correlated with mortality for COVID-19, and is therefore used in prognosis tools. In a current COVID-19 clinical randomized trial (CRT), the blood level of LDH was selected as an inclusion criterion. However, LDH decreased during the pandemic; hence, the impact of this decrease on the prognostic value of LDH for mortality was evaluated. Methods: Data on LDH levels in 843 patients were obtained and analyzed. Relative risk, standard error and receiver operating characteristic curves were calculated for two cutoff values. Results: Relative risk lost validity and the area under the curve narrowed by trimester during the pandemic. Conclusion: The progressive decrease in LDH impacted the capacity to predict mortality in COVID-19. More studies are needed to validate this finding and its implications.
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COVID-19 , L-Lactato Deshidrogenasa , Humanos , COVID-19/enzimología , COVID-19/epidemiología , L-Lactato Deshidrogenasa/metabolismo , Pandemias , Pronóstico , Estudios Retrospectivos , Curva ROCRESUMEN
The Amazonas was one of the most heavily affected Brazilian states by the COVID-19 epidemic. Despite a large number of infected people, particularly during the second wave associated with the spread of the Variant of Concern (VOC) Gamma (lineage P.1), SARS-CoV-2 continues to circulate in the Amazonas. To understand how SARS-CoV-2 persisted in a human population with a high immunity barrier, we generated 1,188 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st January to 6th July 2021, of which 38 were vaccine breakthrough infections. Our study reveals a sharp increase in the relative prevalence of Gamma plus (P.1+) variants, designated Pango Lineages P.1.3 to P.1.6, harboring two types of additional Spike changes: deletions in the N-terminal (NTD) domain (particularly Δ144 or Δ141-144) associated with resistance to anti-NTD neutralizing antibodies or mutations at the S1/S2 junction (N679K or P681H) that probably enhance the binding affinity to the furin cleavage site, as suggested by our molecular dynamics simulations. As lineages P.1.4 (S:N679K) and P.1.6 (S:P681H) expanded (Re > 1) from March to July 2021, the lineage P.1 declined (Re < 1) and the median Ct value of SARS-CoV-2 positive cases in Amazonas significantly decreases. Still, we did not find an increased incidence of P.1+ variants among breakthrough cases of fully vaccinated patients (71%) in comparison to unvaccinated individuals (93%). This evidence supports that the ongoing endemic transmission of SARS-CoV-2 in the Amazonas is driven by the spread of new local Gamma/P.1 sublineages that are more transmissible, although not more efficient to evade vaccine-elicited immunity than the parental VOC. Finally, as SARS-CoV-2 continues to spread in human populations with a declining density of susceptible hosts, the risk of selecting more infectious variants or antibody evasion mutations is expected to increase. IMPORTANCE The continuous evolution of SARS-CoV-2 is an expected phenomenon that will continue to happen due to the high number of cases worldwide. The present study analyzed how a Variant of Concern (VOC) could still circulate in a population hardly affected by two COVID-19 waves and with vaccination in progress. Our results showed that the answer behind that was a new generation of Gamma-like viruses, which emerged locally carrying mutations that made it more transmissible and more capable of spreading, partially evading prior immunity triggered by natural infections or vaccines. With thousands of new cases daily, the current pandemics scenario suggests that SARS-CoV-2 will continue to evolve and efforts to reduce the number of infected subjects, including global equitable access to COVID-19 vaccines, are mandatory. Thus, until the end of pandemics, the SARS-CoV-2 genomic surveillance will be an essential tool to better understand the drivers of the viral evolutionary process.
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COVID-19/enzimología , Furina/metabolismo , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Secuencias de Aminoácidos , Brasil/epidemiología , COVID-19/epidemiología , COVID-19/transmisión , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Furina/genética , Genómica , Humanos , Mutación , Filogenia , SARS-CoV-2/clasificación , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as coronavirus disease 2019 (COVID-19) causes cytokine release syndrome (CRS), leading to acute respiratory distress syndrome (ARDS), acute kidney and cardiac injury, liver dysfunction, and multiorgan failure. Although several studies have discussed the role of 5-lipoxygenase (5-LOX) in viral infections, such as influenzae and SARS, it remains unexplored in the pathophysiology of COVID-19. 5-LOX acts on free arachidonic acid (AA) to form proinflammatory leukotrienes (LTs). Of note, numerous cells involved with COVID-19 (e.g., inflammatory and smooth muscle cells, platelets, and vascular endothelium) widely express leukotriene receptors. Moreover, 5-LOX metabolites induce the release of cytokines (e.g., tumour necrosis factor-α [TNF-α], interleukin-1α [IL-1α], and interleukin-1ß [IL-1ß]) and express tissue factor on cell membranes and activate plasmin. Since macrophages, monocytes, neutrophils, and eosinophils can express lipoxygenases, activation of 5-LOX and the subsequent release of LTs may contribute to the severity of COVID-19. This review sheds light on the potential implications of 5-LOX in SARS-CoV-2-mediated infection and the anticipated therapeutic role of 5-LOX inhibitors.
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Araquidonato 5-Lipooxigenasa/metabolismo , Tratamiento Farmacológico de COVID-19 , COVID-19/enzimología , COVID-19/fisiopatología , Interleucinas/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , SARS-CoV-2 , Animales , Ácido Araquidónico/metabolismo , Síndrome de Liberación de Citoquinas , Citocinas/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Inflamación , Leucotrienos/metabolismo , Resultado del Tratamiento , Virosis/tratamiento farmacológicoRESUMEN
Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.
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COVID-19/metabolismo , Pulmón/fisiopatología , Metaloproteinasas de la Matriz/metabolismo , Proteínas Quinasas/metabolismo , Síndrome de Dificultad Respiratoria/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , COVID-19/enzimología , COVID-19/fisiopatología , COVID-19/virología , Comorbilidad , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/metabolismo , Inflamación/patología , Pulmón/enzimología , Pulmón/metabolismo , Pulmón/virología , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Síndrome de Dificultad Respiratoria/enzimología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/patogenicidad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes de COVID-19 disease use as a principal receptor the angiotensin-converting enzyme-2 (ACE2). It has been suggested that dipeptidyl peptidase-4 (DPP4) can be another possible receptor for this virus. The present study aimed to establish if the DPP4 levels and DPP4 polymorphisms are associated with COVID-19 disease and its severity. METHODS: The study included 107 COVID-19 patients and 263 matched-healthy controls. Fifty patients required invasive mechanical ventilation. The DPP4 was quantified in serum using the Bioplex system. Based on the previous results and the functional prediction analysis, we select for the study 5 DPP4 polymorphisms (rs12617336, rs12617656, rs1558957, rs3788979, and rs17574) and these were determined using the 5´exonuclease TaqMan assays. RESULTS: Low levels of DPP4 were observed in COVID-19 patients (46.5 [33.1-57.7] ng/mL) when compared to healthy controls (125.3 [100.3-157.3] ng/mL) (P < 0.0001). Also, patients that required mechanical ventilation showed lower DPP4 levels (42.8 [29.8-56.9] ng/mL) than those that did not need this procedure (49.2 [39.9-65.6] ng/mL) (P = 0.012). DPP4 levels correlated negatively with age, fibrinogen, and platelet levels, and positively with albumin, alanine aminotransferase, and percentage of neutrophils. The DPP4 rs3788979 polymorphism was associated with a high risk of COVID-19 disease and, the TT genotype carriers had the lowest DPP4 levels. CONCLUSIONS: In summary, in the present study, an association of low levels of DPP4 with COVID-19 disease and severity was found. The association of the DPP4 rs3788979 polymorphism with COVID-19 is also reported.
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COVID-19/genética , Dipeptidil Peptidasa 4/genética , Adulto , Anciano , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/enzimología , COVID-19/epidemiología , COVID-19/patología , Dipeptidil Peptidasa 4/metabolismo , Femenino , Frecuencia de los Genes , Humanos , Masculino , México/epidemiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Coronavirus desease 2019 (COVID-19) is responsible for more than 1.80 M deaths worldwide. A Quantitative Structure-Activity Relationships (QSAR) model is developed based on experimental pIC50 values reported for a structurally diverse dataset. A robust model with only five descriptors is found, with values of R2 = 0.897, Q2LOO = 0.854, and Q2ext = 0.876 and complying with all the parameters established in the validation Tropsha's test. The analysis of the applicability domain (AD) reveals coverage of about 90% for the external test set. Docking and molecular dynamic analysis are performed on the three most relevant biological targets for SARS-CoV-2: main protease, papain-like protease, and RNA-dependent RNA polymerase. A screening of the DrugBank database is executed, predicting the pIC50 value of 6664 drugs, which are IN the AD of the model (coverage = 79%). Fifty-seven possible potent anti-COVID-19 candidates with pIC50 values > 6.6 are identified, and based on a pharmacophore modelling analysis, four compounds of this set can be suggested as potent candidates to be potential inhibitors of SARS-CoV-2. Finally, the biological activity of the compounds was related to the frontier molecular orbitals shapes.
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Antivirales/química , COVID-19/enzimología , Proteasas 3C de Coronavirus , Inhibidores de Cisteína Proteinasa/química , Bases de Datos de Compuestos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , ARN Polimerasa Dependiente del ARN , SARS-CoV-2/enzimología , Antivirales/uso terapéutico , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/química , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Relación Estructura-Actividad Cuantitativa , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/química , Tratamiento Farmacológico de COVID-19RESUMEN
In the current pandemic situation raised due to COVID-19, drug reuse is emerging as the first line of treatment. The viral agent that causes this highly contagious disease and the acute respiratory syndrome coronavirus (SARS-CoV) share high nucleotide similarity. Therefore, it is structurally expected that many existing viral targets are similar to the first SARS-CoV, probably being inhibited by the same compounds. Here, we selected two viral proteins based on their vital role in the viral life cycle: Structure of the main protease SARS-CoV-2 and the structural base of the SARS-CoV-2 protease 3CL, both supporting the entry of the virus into the human host. The approved drugs used were azithromycin, ritonavir, lopinavir, oseltamivir, ivermectin and heparin, which are emerging as promising agents in the fight against COVID-19. Our hypothesis behind molecular coupling studies is to determine the binding affinities of these drugs and to identify the main amino acid residues that play a fundamental role in their mechanism of action. Additional studies on a wide range of FDA-approved drugs, including a few more protein targets, molecular dynamics studies, in vitro and biological in vivo evaluation are needed to identify combination therapy targeted at various stages of the viral life cycle. In our experiment in silico, based mainly on the molecular coupling approach, we investigated six different types of pharmacologically active drugs, aiming at their potential application alone or in combination with the reuse of drugs. The ligands showed stable conformations when analyzing the affinity energy in both proteases: ivermectin forming a stable complex with the two proteases with values -8.727 kcal/mol for Main Protease and -9.784 kcal/mol for protease 3CL, Heparin with values of -7.647 kcal/mol for the Main protease and -7.737 kcal/mol for the 3CL protease. Both conform to the catalytic site of the proteases. Our studies can provide an insight into the possible interactions between ligands and receptors, through better conformation. The ligands ivermectin, heparin and ritonavir showed stable conformations. Our in-silica docking data shows that the drugs we have identified can bind to the binding compartment of both proteases, this strongly supports our hypothesis that the development of a single antiviral agent targeting Main protease, or 3CL protease, or an agent used in combination with other potential therapies, it could provide an effective line of defense against diseases associated with coronaviruses.
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Azitromicina/química , COVID-19/enzimología , Proteasas 3C de Coronavirus/química , Heparina/química , Ivermectina/química , Lopinavir/química , Oseltamivir/química , Ritonavir/química , SARS-CoV-2/enzimología , Humanos , Simulación del Acoplamiento MolecularRESUMEN
INTRODUCTION: Coronavirus disease 2019 (COVID-19) has brought great challenges to global public health. However, a comprehensive analysis of the relationship between liver biochemical parameters and COVID-19 mortality is quite limited. METHODS: We searched the following electronic databases: PubMed, Embase, Cochrane Library, Web of Science, Scopus, Wanfang and China National Knowledge Infrastructure database until May 5, 2020. STATA software was used for the statistical analyses. RESULTS: A total of 25 studies involving 5971 COVID-19 patients were included in our analysis. Compared with non-survivors, survivors had lower levels of aspartate aminotransferase (AST) (weighted mean difference [WMD]=-16.71U/L, 95%CI=[-21.03,-12.40], P<0.001), alanine transaminase (ALT) (WMD=-5.20U/L, 95%CI=[-8.00,-2.41], P<0.001), total bilirubin (TBIL) (WMD=4.40µmol/L, 95%CI=[-5.11,-3.70], P<0.001) and lactic dehydrogenase (LDH) (WMD=-252.44U/L, 95%CI=[-289.57,-215.30], P<0.001), and higher albumin (ALB) level (WMD=4.47g/L, 95%CI=[3.47,5.47], P<0.001). Besides, survivors had lower proportions of these abnormally increased parameters (AST: OR=0.25, 95%CI=[0.15,0.41], P<0.001; ALT: OR=0.49, 95%CI=[0.37,0.64], P<0.001; TBIL: (OR=0.20, 95%CI=[0.12,0.34], P<0.001; LDH, OR=0.09, 95%CI=[0.06,0.14], P<0.001), and lower proportion of abnormally decreased ALB (OR=0.16, 95%CI=[0.07,0.38], P<0.001). Meta-analysis based on standard mean difference and sensitivity analysis did not change the conclusions. Egger test did not detect the presence of publication bias. CONCLUSIONS: Liver biochemical parameters were strongly correlated with COVID-19 mortality. Measurement of these liver biochemical parameters might assist clinicians to evaluate the prognosis of COVID-19.