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1.
Front Endocrinol (Lausanne) ; 12: 688071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489863

RESUMO

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly symptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender (p<0.05). G-carrier genotypes of both polymorphisms were also associated with higher mortality (p< 0.05) and higher severity of COVID-19 in dyslipidemic (p<0.05) and type 2 diabetic patients (p< 0.01). The association of G alleles with disease severity was adjusted for age, sex, BMI and number of comorbidities, suggesting that both the metabolic comorbidities and the G allele act synergistically on COVID-19 outcome. Although we did not find a direct association between serum ACE levels and COVID-19 severity, we found higher levels of ACE in the serum of patients with the GG genotype of rs4341 and rs4343 (p<0.05), what could explain the higher susceptibility to develop severe forms of the disease in patients with the GG genotype, in addition to hypertension and dyslipidemia. In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.


Assuntos
COVID-19/genética , Diabetes Mellitus/genética , Dislipidemias/genética , Variação Genética/genética , Hipertensão/genética , Peptidil Dipeptidase A/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Hospitalização/tendências , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , Índice de Gravidade de Doença , Espanha/epidemiologia
2.
Front Cell Infect Microbiol ; 11: 707194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434902

RESUMO

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy (ΔΔG) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Simulação de Dinâmica Molecular , Mutação , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
3.
J Transl Med ; 19(1): 358, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412632

RESUMO

BACKGROUND: SARS-CoV-2, which has brought a huge negative impact on the world since the end of 2019, is reported to invade cells using the spike (S) protein to bind to angiotensin-converting enzyme II (ACE2) receptors on human cells while the transmembrane protease serine 2 (TMPRSS2) is the key protease that activates the S protein, which greatly facilitates the entry of SARS-CoV-2 into target cells. In our previous study, it was observed that the positive rate of SARS-CoV-2 nucleic acids in saliva was higher in male and the elderly COVID-19 patients, suggesting that the susceptibility of oral tissues to SARS-CoV-2 may be related to gender and age. This research aimed to further investigate the SARS-CoV-2 susceptibility in oral tissues and influencing factors from the perspective of ACE2 and TMPRSS2, which were two proteins closely associated with SARS-CoV-2 infection. METHODS: Immunofluorescence was used to find the localization of ACE2 and TMPRSS2 in oral mucosal tissues. Transcriptomic sequencing data of several datasets were then collected to analysis the relationship between the expressions of ACE2 and TMPRSS2 with the age and gender of patients. Furthermore, oral tissues from patients with different ages and genders were collected. Immunohistochemistry staining, qRT-PCR and western blot were performed to explore the relationship between expression levels of ACE2 and TMPRSS2 and patient age as well as gender. RESULTS: The results showed that the two proteins were able to be co-expressed in the epithelial cells of oral tissues, and their expression levels were higher in the relatively elderly group than those in relatively younger group. Male oral epithelial cells exhibited higher level of TMPRSS2. CONCLUSIONS: Our findings comprehensively confirmed the existence of ACE2 and TMPRSS2 in oral tissues and clarify the relationship between the expression levels with human age and gender for the first time, providing evidence for possible entry routes of SARS-CoV-2 and the influencing factors of SARS-CoV-2 colonization in oral cavity. Thus, the oral mucosa might be at potential risk of infection by SARS-CoV-2, especially in male or elderly patients. Using saliva to detect the nucleic acids of SARS-CoV-2 may be more accurate for elder male COVID-19 patients.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Idoso , Enzima de Conversão de Angiotensina 2 , Células Epiteliais , Feminino , Humanos , Masculino , Peptidil Dipeptidase A/genética , SARS-CoV-2 , Serina Endopeptidases/genética , Fatores Sexuais , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus
4.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359878

RESUMO

Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman's p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman's Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.


Assuntos
Peptidil Dipeptidase A/metabolismo , Idoso , Feminino , Humanos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Peptidil Dipeptidase A/análise , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Processamento de Proteína Pós-Traducional
5.
Medicina (Kaunas) ; 57(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34441050

RESUMO

Background and objective: Insertion/deletion polymorphisms of angiotensin-converting enzyme (ACE) have been previously described in association with adult respiratory distress syndrome (ARDS) and correlated to outcome. The ACE deletion/deletion(D/D)genotype represents a marker of thrombosis in subjects apparently without predisposing factors and/or traditional thrombophilic alterations and increases the risk of venous thromboembolism in subjects in whom a thrombogenic condition occurs. Thrombosis seems to play a role very early in the disease caused by SARS-CoV-2, in particular in those with severe COVID-19 pneumonia. The counterbalance between angiotensin-converting enzyme (ACE) and ACE2 activities in COVID-19 disease may play a crucial role in the thrombo-inflammatory process. We hypothesised that a genetic predisposition could condition the severity and complications of SARS-CoV-2 infection. Materials and methods: We conducted a spontaneous, single centre observational study in the Sub-Intensive Care Unit of A.O.R.N. Ospedali dei Colli, Cotugno Hospital, Naples (Italy). In this study, we performed genetic screening for ACE D/D genotype and other thrombophilic mutations in 20 patients affected by ARDS related to COVID-19 pneumonia, compared to 19 age- and sex-matched healthy controls. Results: All tested patients had multiple polymorphisms and, in particular, a significantly higher prevalence of ACE D/D polymorphism in severe COVID-19 patients Conclusion: We found that the majority of patients who tested positive for ACE D-D genotype and who were not associated with other risk factors for VTE showed an evolution to ARDS. This finding could have a predicting role in the selection of patients more prone to developing severe COVID-19 during clinical observation in emergency department.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Adulto , Serviço Hospitalar de Emergência , Genótipo , Humanos , Peptidil Dipeptidase A/genética , Fatores de Risco , SARS-CoV-2
6.
Comput Biol Med ; 135: 104654, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34346317

RESUMO

COVID-19 is an infectious and pathogenic viral disease caused by SARS-CoV-2 that leads to septic shock, coagulation dysfunction, and acute respiratory distress syndrome. The spreading rate of SARS-CoV-2 is higher than MERS-CoV and SARS-CoV. The receptor-binding domain (RBD) of the Spike-protein (S-protein) interacts with the human cells through the host angiotensin-converting enzyme 2 (ACE2) receptor. However, the molecular mechanism of pathological mutations of S-protein is still unclear. In this perspective, we investigated the impact of mutations in the S-protein and their interaction with the ACE2 receptor for SAR-CoV-2 viral infection. We examined the stability of pathological nonsynonymous mutations in the S-protein, and the binding behavior of the ACE2 receptor with the S-protein upon nonsynonymous mutations using the molecular docking and MM_GBSA approaches. Using the extensive bioinformatics pipeline, we screened the destabilizing (L8V, L8W, L18F, Y145H, M153T, F157S, G476S, L611F, A879S, C1247F, and C1254F) and stabilizing (H49Y, S50L, N501Y, D614G, A845V, and P1143L) nonsynonymous mutations in the S-protein. The docking and binding free energy (ddG) scores revealed that the stabilizing nonsynonymous mutations show increased interaction between the S-protein and the ACE2 receptor compared to native and destabilizing S-proteins and that they may have been responsible for the virulent high level. Further, the molecular dynamics simulation (MDS) approach reveals the structural transition of mutants (N501Y and D614G) S-protein. These insights might help researchers to understand the pathological mechanisms of the S-protein and provide clues regarding mutations in viral infection and disease propagation. Further, it helps researchers to develop an efficient treatment approach against this SARS-CoV-2 pandemic.


Assuntos
COVID-19 , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Peptidil Dipeptidase A/genética , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/genética
7.
Clin Lab ; 67(7)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34258966

RESUMO

BACKGROUND: Respiratory epithelium expressing angiotensin-converting enzyme 2 (ACE2) is the entry for novel coronavirus (SARS-CoV-2), pathogen of the COVID-19 pneumonia outbreak, although a few recent studies have found different ACE2 expression in lung tissue of smokers. The effect of smoking on ACE2 expression and COVID-19 is still not clear. So, we did this research to determine the effect of smoking on ACE2 expression pattern and its relationship with the risk and severity of COVID-19. METHODS: The clinical data of COVID-19 patients with smoking and non-smoking were analyzed, and ACE2 expression of respiratory and digestive mucosa epithelia from smoker and non-smoker patients or healthy subjects were detected by immunohistochemical (IHC) staining. RESULTS: Of all 295 laboratory-confirmed COVID-19 patients, only 24 (8.1%) were current smokers with moderate smoking or above, which accounted for 54.2% of severe cases with higher mortality than non-smokers (8.3% vs. 0.4%, p = 0.018). Data analysis showed the proportion of smokers in COVID-19 patients was lower than that in general population of China (Z = 11.65, P < 0.001). IHC staining showed ACE2 expression in respiratory and digestive epithelia of smokers were generally downregulated. CONCLUSIONS: The proportion of smokers in COVID-19 patients was lower, which may be explained by ACE2 downregulation in respiratory mucosa epithelia. However, smoking COVID-19 patients accounted for a higher proportion in severe cases and higher mortality than for non-smoking COVID-19 patients, which needs to be noted.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Enzima de Conversão de Angiotensina 2 , China/epidemiologia , Humanos , Peptidil Dipeptidase A/genética , SARS-CoV-2 , Fumar/efeitos adversos
10.
Genes (Basel) ; 12(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209818

RESUMO

This study builds a coronavirus knowledge graph (KG) by merging two information sources. The first source is Analytical Graph (AG), which integrates more than 20 different public datasets related to drug discovery. The second source is CORD-19, a collection of published scientific articles related to COVID-19. We combined both chemo genomic entities in AG with entities extracted from CORD-19 to expand knowledge in the COVID-19 domain. Before populating KG with those entities, we perform entity disambiguation on CORD-19 collections using Wikidata. Our newly built KG contains at least 21,700 genes, 2500 diseases, 94,000 phenotypes, and other biological entities (e.g., compound, species, and cell lines). We define 27 relationship types and use them to label each edge in our KG. This research presents two cases to evaluate the KG's usability: analyzing a subgraph (ego-centered network) from the angiotensin-converting enzyme (ACE) and revealing paths between biological entities (hydroxychloroquine and IL-6 receptor; chloroquine and STAT1). The ego-centered network captured information related to COVID-19. We also found significant COVID-19-related information in top-ranked paths with a depth of three based on our path evaluation.


Assuntos
COVID-19 , Bases de Conhecimento , COVID-19/epidemiologia , COVID-19/etiologia , Cloroquina/farmacologia , Gráficos por Computador , Bases de Dados Factuais , Doença pelo Vírus Ebola/tratamento farmacológico , Humanos , Hidroxicloroquina/farmacologia , Reconhecimento Automatizado de Padrão , Peptidil Dipeptidase A/genética , PubMed , Receptores de Interleucina-6/sangue , SARS-CoV-2 , Fator de Transcrição STAT1
11.
Biophys J ; 120(14): 2785-2792, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34214538

RESUMO

The entry of the severe acute respiratory syndrome coronavirus 2 virus in human cells is mediated by the binding of its surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor. A 23-residue long helical segment (SBP1) at the binding interface of human ACE2 interacts with viral spike protein and therefore has generated considerable interest as a recognition element for virus detection. Unfortunately, emerging reports indicate that the affinity of SBP1 to the receptor-binding domain of the spike protein is much lower than that of the ACE2 receptor itself. Here, we examine the biophysical properties of SBP1 to reveal factors leading to its low affinity for the spike protein. Whereas SBP1 shows good solubility (solubility > 0.8 mM), circular dichroism spectroscopy shows that it is mostly disordered with some antiparallel ß-sheet content and no helicity. The helicity is substantial (>20%) only upon adding high concentrations (≥20% v/v) of 2,2,2-trifluoroethanol, a helix promoter. Fluorescence correlation spectroscopy and single-molecule photobleaching studies show that the peptide oligomerizes at concentrations >50 nM. We hypothesized that mutating the hydrophobic residues (F28, F32, and F40) of SBP1, which do not directly interact with the spike protein, to alanine would reduce peptide oligomerization without affecting its spike binding affinity. Whereas the mutant peptide (SBP1mod) shows substantially reduced oligomerization propensity, it does not show improved helicity. Our study shows that the failure of efforts, so far, to produce a short SBP1 mimic with a high affinity for the spike protein is not only due to the lack of helicity but is also due to the heretofore unrecognized problem of oligomerization.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Enzima de Conversão de Angiotensina 2 , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
12.
Ann Saudi Med ; 41(3): 141-146, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34085542

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism may play a role in the pathogenesis of coronavirus-19 disease (COVID-19). OBJECTIVES: Investigate the relationship between ACE I/D polymorphism and the clinical severity of COVID-19. DESIGN: Prospective cohort study. SETTING: Tertiary care hospital. PATIENTS AND METHODS: The study included COVID-19 patients with asymptomatic, mild, and severe disease with clinical data and whole blood samples collected from 1 April 2020 to 1 July 2020. ACE I/D genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. MAIN OUTCOME MEASURE: ACE DD, DI and II genotypes frequencies. SAMPLE SIZE: 90 cases, 30 in each disease severity group. RESULTS: Age and the frequency of general comorbidity increased significantly from the asymptomatic disease group to the severe disease group. Advanced age, diabetes mellitus and presence of ischemic heart disease were independent risk factors for severe COVID-19 [OR and 95 % CI: 1.052 (1.021-1.083), 5.204 (1.006-26.892) and 5.922 (1.109-31.633), respectively]. The ACE II genotype was the dominant genotype (50%) in asymptomatic patients, while the DD genotype was the dominant genotype (63.3 %) in severe disease. The ACE II geno-type was protective against severe COVID-19 [OR and 95% CI: .323 (.112-.929)]. All nine patients (8.9%) who died had severe disease. CONCLUSIONS: The clinical severity of COVID-19 infection may be associated with the ACE I/D polymorphism. LIMITATIONS: Small sample size and single center. CONFLICT OF INTEREST: None.


Assuntos
COVID-19/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Índice de Gravidade de Doença , Adulto , Idoso , Sequência de Bases , COVID-19/diagnóstico , Feminino , Seguimentos , Marcadores Genéticos , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Estudos Prospectivos , Deleção de Sequência
13.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066804

RESUMO

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin-angiotensin-aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.


Assuntos
COVID-19/genética , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Idoso , Alelos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Antígenos HLA/genética , Antígenos HLA/metabolismo , Haplótipos , Humanos , Inflamação/genética , Inflamação/metabolismo , Homem de Neandertal/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Fatores de Risco , Índice de Gravidade de Doença
14.
J Med Virol ; 93(10): 5947-5952, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34170561

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease, and the reason behind the currently ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme (ACE2) has been recognized as the specific receptor of the SARS-CoV-2 virus. Although the possible effect of ACE2 gene polymorphism remains unknown, human ACE2 receptor expression influences SARS-CoV-2 susceptibility and COVID-19 disease outcome. In this study, we aimed to investigate the relationship between ACE gene I/D polymorphism, ACE2 receptor gene polymorphism, and COVID-19 severity. ACE gene insertion/deletion (I/D) polymorphism and ACE2 receptor gene rs2106809 and rs2285666 polymorphisms were determined using polymerase chain reaction (PCR) and PCR-based restriction fragment length polymorphism methods, respectively, in 155 COVID-19 patients who were divided into three groups (mild, moderate, and severe) according to clinical symptoms. However, the distribution of genotype and allele frequencies of ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not statistically significant in all groups. In conclusion, in the study population, ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not associated with the severity of COVID-19 infection. Although ACE2 receptor gene expression may affect the susceptibility to COVID-19, there is no existing evidence that the ACE or ACE2 gene polymorphisms are directly associated with COVID-19 severity. Interindividual differences in COVID-19 severity might be related to epigenetic mechanisms of ACE2 receptor gene expression or variations in other genes suggested to play a critical role in COVID-19 pathogenesis such as pro-inflammatory cytokines and coagulation indicators.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Peptidil Dipeptidase A/genética , Adulto , Idoso , COVID-19/diagnóstico , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Resultados Negativos , Polimorfismo de Nucleotídeo Único , SARS-CoV-2 , Índice de Gravidade de Doença
15.
Biomed Khim ; 67(3): 244-250, 2021 May.
Artigo em Russo | MEDLINE | ID: mdl-34142531

RESUMO

Computer simulation has been used to identify peptides that mimic the natural target of the SARS-CoV-2 coronavirus spike (S) protein, the angiotensin converting enzyme type 2 (ACE2) cell receptor. Based on the structure of the complex of the protein S receptor-binding domain (RBD) and ACE2, the design of chimeric molecules consisting of two 22-23-mer peptides linked to each other by disulfide bonds was carried out. The chimeric molecule X1 was a disulfide dimer, in which edge cysteine residues in the precursor molecules h1 and h2 were connected by the S-S bond. In the chimeric molecule X2, the disulfide bond was located in the middle of the molecule of each of the precursor peptides. The precursors h1 and h2 modelled amino acid sequences of α1- and α2-helices of the extracellular peptidase domain of ACE2, respectively, keeping intact most of the amino acid residues involved in the interaction with RBD. The aim of the work was to evaluate the binding efficiency of chimeric molecules and their RBD-peptides (particularly in dependence of the middle and edge methods of fixing the initial peptides h1 and h2). The proposed polypeptides and chimeric molecules were synthesized by chemical methods, purified (to 95-97% purity), and characterized by HPLC and MALDI-TOF mass spectrometry. The binding of the peptides to the SARS-CoV-2 RBD was evaluated by microthermophoresis with recombinant domains corresponding in sequence to the original Chinese (GenBank ID NC_045512.2) and the British (B. 1.1.7, GISAID EPI_ISL_683466) variants. Binding to the original RBD of the Chinese variant was detected in three synthesized peptides: linear h2 and both chimeric variants. Chimeric peptides were also bound to the RBD of the British variant with micromolar constants. The antiviral activity of the proposed peptides in Vero cell culture was also evaluated.


Assuntos
COVID-19 , Peptidil Dipeptidase A , Enzima de Conversão de Angiotensina 2 , Simulação por Computador , Humanos , Peptídeos , Peptidil Dipeptidase A/genética , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
17.
BMC Med Genomics ; 14(1): 138, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030677

RESUMO

BACKGROUND: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. METHODS: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. RESULTS: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. CONCLUSIONS: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.


Assuntos
COVID-19/genética , COVID-19/virologia , Regulação da Expressão Gênica , Peptidil Dipeptidase A/genética , Receptores de Reconhecimento de Padrão/genética , Receptores Virais/genética , SARS-CoV-2/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Derme/patologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , RNA-Seq , Receptores Virais/metabolismo , Adulto Jovem
18.
J Phys Chem B ; 125(21): 5537-5548, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33979162

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ligação Proteica
19.
Nanoscale ; 13(20): 9364-9370, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-33999091

RESUMO

The widespread coronavirus disease 2019 (COVID-19) has been declared a global health emergency. As one of the most important targets for antibody and drug developments, the Spike RBD-ACE2 interface has received extensive attention. Here, using molecular dynamics simulations, we explicitly analyzed the energetic features of the RBD-ACE2 complex of both SARS-CoV and SARS-CoV-2. Despite the high structural similarity, the binding strength of SARS-CoV-2 to the ACE2 receptor is estimated to be -16.35 kcal mol-1 stronger than that of SARS-CoV. Energy decomposition analyses identified three binding patches in SARS-CoV-2 RBD and eleven key residues (F486, Y505, N501, Y489, Q493, L455, etc.), which are believed to be the main targets for drug development. The dominating forces arise from van der Waals attractions and dehydration of these residues. Compared with SARS-CoV, we found seven mutational sites (K417, L455, A475, G476, E484, Q498 and V503) on SARS-CoV-2 that unexpectedly weakened the RBD-ACE2 binding. Interestingly, the E484 site is recognized to be the most repulsive residue at the RBD-ACE2 interface, indicating that from the energy point of view, a mutation of E484 would be beneficial to RBD-ACE2 binding. This is in line with recent findings that it is mutated by lysine (E484K mutation) in the rapidly spreading variants of COVID-19 belonging to the B.1.351 and P.1 lineages. In addition, this mutation is reported to cause virus neutralization escapes from highly neutralizing COVID-19 convalescent plasma. Thus, further efforts are required to probe its functional relevance. Overall, our results present a systematic understanding of the energetic binding features of SARS-CoV-2 RBD with the ACE2 receptor, which can provide a valuable insight for the design of SARS-CoV-2 drugs and identification of cross-active antibodies.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Enzima de Conversão de Angiotensina 2 , Sítios de Ligação , COVID-19/terapia , Humanos , Imunização Passiva , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
20.
Gene ; 790: 145696, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33964377

RESUMO

BACKGROUND AND AIMS: Hemorrhagic stroke (HS) results in significant mortality and disability worldwide. Angiotensin Converting Enzyme (ACE) is responsible for blood pressure regulation and vascular homeostasis. Our objective was to conduct a comprehensive meta-analysis for ascertaining the association of ACE I/D polymorphism with HS since a number of studies depicted inconclusive evidence. METHODS: Literature search was performed till July 10, 2020 in PubMed, EMBASE, Cochrane, Chinese National Knowledge Information and Google Scholar databases with keywords: ('Angiotensin Converting Enzyme' OR 'ACE') AND ('Single Nucleotide polymorphisms' OR 'SNP') AND ('Hemorrhagic stroke or 'HS'). Pooled Odds Ratio (OR) and 95% Confidence Interval (CI) were determined for gene-disease association using either fixed (when I2 < 50%) or random effect (when I2 > 50%) models. Risk of bias in studies was assessed using funnel plots and sensitivity analyses. Statistical analysis was performed using STATA version 13.0 software. RESULTS: A total of 53 studies having 5186 HS and 7347 healthy control subjects were included in our meta-analysis. Pooled analyses showed that ACE I/D gene polymorphism had significant association with risk of HS in overall study population [(dominant model: OR = 1.29, 95% CI = 1.12-1.50 & recessive model: OR = 1.79, 95% CI = 1.46-2.20)]. Population subgroup analyses further revealed significant relationship of ACE I/D polymorphism with ICH in Asians (recessive: OR 1.97, 95% CI = 1.57-2.47) but not in Caucasians (recessive: OR 1.02, 95% CI = 0.76-1.36). CONCLUSION: This meta-analysis suggests that ACE I/D polymorphism may lead to risk of HS and can be a potential biomarker for HS susceptibility especially in Asian population.


Assuntos
AVC Hemorrágico/etiologia , Mutação INDEL , Peptidil Dipeptidase A/genética , AVC Hemorrágico/patologia , Humanos
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