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1.
Ann Lab Med ; 41(2): 129-138, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33063674

RESUMO

Since its first report in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged as a pandemic affecting nearly all countries worldwide. As the COVID-19 pandemic progresses, the need to identify genetic risk factors for susceptibility to this serious illness has emerged. Host genetic factors, along with other risk factors may help determine susceptibility to respiratory tract infections. It is hypothesized that the ACE2 gene, encoding angiotensin-converting enzyme 2 (ACE2), is a genetic risk factor for SARS-CoV-2 infection and is required by the virus to enter cells. Together with ACE2, transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-4 (DPP4) also play an important role in disease severity. Evaluating the role of genetic variants in determining the direction of respiratory infections will help identify potential drug target candidates for further study in COVID-19 patients. We have summarized the latest reports demonstrating that ACE2 variants, their expression, and epigenetic factors may influence an individual's susceptibility to SARS-CoV-2 infection and disease outcome.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/patologia , Variação Genética , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Índice de Gravidade de Doença
2.
Sci Total Environ ; 750: 141532, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858292

RESUMO

Coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly developed into a pandemic throughout the world. This disease is a highly infectious novel coronavirus and can affect people of all ages. Previous reports observed that particulate matter (PM) provided a platform for intermixing with viruses (i.e., influenza). However, the role of PM in SARS-CoV-2 transmission remains unclear. In this paper, we propose that PM plays a direct role as a "carrier" of SARS-CoV-2. SARS-CoV-2 is reported to have a high affinity for the angiotensin-converting enzyme 2 (ACE2) receptor. Indirectly, exposure to PM increases ACE2 expression in the lungs which facilitates SARS-CoV-2 viral adhesion. Thus, the high risk of SARS-CoV-2 in heavily polluted regions can be explained by upregulation of ACE2 caused by PM. PM could be both a direct and indirect transmission model for SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus , Coronavirus , Pandemias , Pneumonia Viral , Betacoronavirus , Humanos , Material Particulado , Peptidil Dipeptidase A/metabolismo
3.
Int J Mol Sci ; 21(21)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158276

RESUMO

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus-host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein-protein interfaces responsible for virus entry and infection transmission.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Receptores Virais/metabolismo , Transdução de Sinais , Internalização do Vírus
4.
PLoS One ; 15(11): e0241168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33170884

RESUMO

The SARS-CoV-2 virion responsible for the current world-wide pandemic COVID-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD) within its distal, prefusion S1 domain. The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-CoV-2 Spike protein in its static prefusion state based on two recent and independent experimental structure publications. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called "glue" points) between residues in the Up and Down state protomers. The S2 proximal, fusion domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer's intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. This included, for example, a key RBD residue ARG357 in the Up-Down interaction and a three residue sequence ALA520-PRO521-ALA522, associated with a turn structure in the RBD of the Up state protomer, acting as a stabilizing interaction with the NTD of its neighbor protomer. Additionally, our intra chain dominant energy mappings within each protomer, identified a significant "glue" point or possible "latch" for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the amino acid R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-CoV-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. We conducted preliminary molecular dynamics simulations across 0.1 µ seconds to see if this latch provided structural stability and indeed found that a single point mutation (Q564G) resulted in the latch releasing transforming the protomer from the Down to the Up state conformation. Full trimeric Spike protein studies of the same mutation across all protomers, however, did not exhibit latch release demonstrating the critical importance of interchain interactions across the S1 domain, including RBD-NTD neighboring chain interactions. Therapies aimed at disrupting these noncovalent interactions could be a viable route for the physico-chemical mitigation of this deadly virion.


Assuntos
Betacoronavirus/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Mutação Puntual , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Termodinâmica
5.
Clin Sci (Lond) ; 134(21): 2851-2871, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33146371

RESUMO

Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Receptores Virais/metabolismo , Internalização do Vírus , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Conformação Proteica , Receptores Virais/química , Relação Estrutura-Atividade
6.
Nat Commun ; 11(1): 5588, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33149112

RESUMO

The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production is hampered by long development times and costly production. Here, we report the rapid isolation and characterization of nanobodies from a synthetic library, known as sybodies (Sb), that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Several binders with low nanomolar affinities and efficient neutralization activity were identified of which Sb23 displayed high affinity and neutralized pseudovirus with an IC50 of 0.6 µg/ml. A cryo-EM structure of the spike bound to Sb23 showed that Sb23 binds competitively in the ACE2 binding site. Furthermore, the cryo-EM reconstruction revealed an unusual conformation of the spike where two RBDs are in the 'up' ACE2-binding conformation. The combined approach represents an alternative, fast workflow to select binders with neutralizing activity against newly emerging viruses.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/prevenção & controle , Anticorpos de Domínio Único/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Microscopia Crioeletrônica , Humanos , Testes de Neutralização , Ligação Proteica , Conformação Proteica , Domínios Proteicos/imunologia , Receptores Virais/metabolismo
7.
Clin Sci (Lond) ; 134(21): 2791-2805, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33135725

RESUMO

Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Nefropatias/enzimologia , Rim/enzimologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Receptores Virais/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/virologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Diabetes Mellitus/enzimologia , Diabetes Mellitus/fisiopatologia , História do Século XXI , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Pandemias , Peptidil Dipeptidase A/história , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/virologia , Receptores Virais/história
8.
Clin Sci (Lond) ; 134(21): 2823-2833, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33140827

RESUMO

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Betacoronavirus/patogenicidade , Infecções por Coronavirus/enzimologia , Absorção Intestinal , Mucosa Intestinal/enzimologia , Proteínas de Membrana Transportadoras/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/enzimologia , Internalização do Vírus , Animais , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Multimerização Proteica
10.
J Renin Angiotensin Aldosterone Syst ; 21(4): 1470320320972018, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33169644

RESUMO

In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).


Assuntos
Angiotensina I/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/virologia , Angiotensina I/fisiologia , Animais , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Fragmentos de Peptídeos/fisiologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
11.
J Mol Model ; 26(12): 338, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175236

RESUMO

A novel coronavirus (SARS-CoV-2) identified in Wuhan state of China in 2019 is the causative agent of deadly disease COVID-19. It has spread across the globe (more than 210 countries) within a short period. Coronaviruses pose serious health threats to both humans and animals. A recent publication reported an experimental 3D complex structure of the S protein of SARS-CoV-2 showed that the ectodomain of the SARS-CoV-2 S protein binds to the peptidase domain (PD) of human ACE2 with a dissociation constant (Kd) of ~ 15 nM. In this study, we focused on inhibitors for ACE2: S protein complex using virtual screening and inhibition studies through molecular docking for over 200,000 natural compounds. Toxicity analysis was also performed for the best hits, and the final complex structures for four complexes were subjected to 400 ns molecular dynamics simulations for stability testing. We found two natural origin inhibitors for the S protein: human ACE2 complex (Andrographolide and Pterostilbene) which displayed better inhibition potential for ACE2 receptor and its binding with the S protein of SARS-CoV-2. Comparative studies were also performed to test and verify that these two drug candidates are also better than hydroxychloroquine which is known to inhibit this complex. However, we needed better potential drug candidates to overcome the side effects of hydroxychloroquine. Supplementary experimental studies need to be carried forward to corroborate the viability of these two new inhibitors for ACE2: S protein complex so as to curb down COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Peptídeo Hidrolases/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/genética , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptídeo Hidrolases/genética , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/genética
13.
Rev. clín. esp. (Ed. impr.) ; 220(8): 507-510, nov. 2020.
Artigo em Espanhol | IBECS | ID: ibc-192189

RESUMO

La eclosión de la pandemia por COVID-19 supone un reto de enormes dimensiones y, dada la gran presencia de diabetes mellitus tipo2 en la población actual, hace que sea un problema de salud en el que centrar nuestros esfuerzos para dar la mejor respuesta a nuestros pacientes, que son más vulnerables al desarrollo de la infección y candidatos a presentar cuadros clínicos más graves. Este documento pretende abordar la relación entre la infección por COVID-19 y la DM2. Para ello analizaremos brevemente qué datos epidemiológicos sustentan esta asociación y, posteriormente, se profundizará en los mecanismos fisiopatológicos que podrían conectar ambas enfermedades


The emergence of the COVID-19 pandemic represents an enormous challenge. Given the considerable presence of type 2 diabetes mellitus in the current population, the pandemic is a health issue that requires an effort to provide better responses to our patients who are more vulnerable to the onset of infection and who are candidates for presenting more severe symptoms. This document attempts to address the relationship between COVID-19 infection and type 2 diabetes mellitus. To this end, we will briefly analyse whether the epidemiological data support this association and, subsequently, go in depth on the pathophysiological mechanisms that might connect the two diseases


Assuntos
Humanos , Infecções por Coronavirus/complicações , Diabetes Mellitus Tipo 2/complicações , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/complicações , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Peptidil Dipeptidase A/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Peptídeos Semelhantes ao Glucagon/agonistas , Insulina/metabolismo , Indicadores de Morbimortalidade , Sistema Renina-Angiotensina/fisiologia
14.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126657

RESUMO

Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin-angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1-9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin-angiotensin system and reducing the pathogen's cell entry could be a promising therapeutic strategy in the struggle against COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Proteína ADAM17/metabolismo , Animais , Betacoronavirus , Permeabilidade Capilar/fisiologia , Humanos , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Pandemias , Edema Pulmonar/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
15.
Molecules ; 25(20)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053830

RESUMO

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein-human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure-activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N-N-C(S)-N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design. Combined, these studies highlighted two molecules among the studied compounds, i.e., 5-(pyrrol-2-yl)-2-(2-methoxyphenylamino)-1,3,4-thiadiazole and 1-(cyclopentanoyl)-4-(3-iodophenyl)-thiosemicarbazide, as the best candidates for the development of future drugs.


Assuntos
Antivirais/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Semicarbazidas/química , Glicoproteína da Espícula de Coronavírus/química , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Humanos , Modelos Estatísticos , Estrutura Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Glicoproteína da Espícula de Coronavírus/metabolismo
16.
Medicine (Baltimore) ; 99(42): e22688, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080715

RESUMO

BACKGROUND: Unknown origin pneumonia has been furiously spreading since the late of December 2019, subsequently spread to approximately all provinces and areas in China and many countries, which was announced as a Public Health Emergency of International Concern by World Health Organization (WHO). The studies on 2019 Corona Virus Disease-19 (COVID-19) conducted from various fields around the world. Herein, the objective of the present study is to summarize the etiology, epidemiology, clinical manifestations, image findings, traceability analysis, and drug development of COVID-19. METHODS: The following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database, VIP Chinese Science and Technology Periodical Database, and Wanfang Data. Other relevant literature will be manually searched as a compliment. We have reviewed etiology, epidemiology, clinical manifestations, image findings, and medication from case reports and retrospective clinical studies relating to COVID-19 published since the outbreak. RESULTS: The coronavirus is closely related to bat coronavirus and pangolin coronavirus. Besides, the infection pathway is confirmed to be the respiratory and digestive systems. The virus indicates person-to-person transmission and some patients present asymptomatic. The elderly have a higher mortality rate. Rapid and sensitive nucleic acid testing is usually used as a basis for diagnosis. Currently, there is no specific vaccine and antiviral drug. Intervention actions such as travel bans and quarantine adopted have effectively reduced the spread of the epidemic. CONCLUSION: This systemic review will provide high-quality evidence to summarize etiology, epidemiology, clinical manifestations, image findings, traceability analysis, drug development in patients with COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Corticosteroides/uso terapêutico , Fatores Etários , Antivirais/uso terapêutico , Betacoronavirus , China , Comorbidade , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/terapia , Citocinas/metabolismo , Humanos , Imunoglobulinas/uso terapêutico , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/etiologia , Pneumonia Viral/terapia , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais
17.
Cell Rep ; 33(4): 108322, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33091382

RESUMO

Biotin-labeled molecular probes, comprising specific regions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, would be helpful in the isolation and characterization of antibodies targeting this recently emerged pathogen. Here, we design constructs incorporating an N-terminal purification tag, a site-specific protease-cleavage site, the probe region of interest, and a C-terminal sequence targeted by biotin ligase. Probe regions include full-length spike ectodomain as well as various subregions, and we also design mutants that eliminate recognition of the angiotensin-converting enzyme 2 (ACE2) receptor. Yields of biotin-labeled probes from transient transfection range from ∼0.5 mg/L for the complete ectodomain to >5 mg/L for several subregions. Probes are characterized for antigenicity and ACE2 recognition, and the structure of the spike ectodomain probe is determined by cryoelectron microscopy. We also characterize antibody-binding specificities and cell-sorting capabilities of the biotinylated probes. Altogether, structure-based design coupled to efficient purification and biotinylation processes can thus enable streamlined development of SARS-CoV-2 spike ectodomain probes.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Coronavirus/imunologia , Sondas Moleculares/imunologia , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Especificidade de Anticorpos/imunologia , Sítios de Ligação de Anticorpos/imunologia , Biotinilação , Microscopia Crioeletrônica , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Receptores Virais/metabolismo
18.
Cells ; 9(11)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33120941

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). The virus invades human cells through the angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway, primarily targeting the human respiratory tract. However, emerging reports of neurological manifestations demonstrate the neuroinvasive potential of SARS-CoV-2. This review highlights the possible routes by which SARS-CoV-2 may invade the central nervous system (CNS) and provides insight into recent case reports of COVID-19-associated neurological disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, and inflammatory-mediated neurological disorders. We hypothesize that SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may be implicated in the development of the observed disorders; however, further research is critical to understand the detailed mechanisms and pathway of infectivity behind CNS pathogenesis.


Assuntos
Betacoronavirus/metabolismo , Barreira Hematoencefálica/fisiopatologia , Barreira Hematoencefálica/virologia , Infecções por Coronavirus/complicações , Doenças do Sistema Nervoso/complicações , Pneumonia Viral/complicações , Internalização do Vírus , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
19.
Geriatr Psychol Neuropsychiatr Vieil ; 18(2): 141-148, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33064080

RESUMO

Coronavirus disease 2019 (COVID-19) is a secondary infectious disease caused by severe acute respiratory syndrome coronavirus 2. The link between cardiovascular disease and COVID-19 appears to be twofold. First, some reports indicate that certain groups of patients are at greater risk of COVID-19, including patients with cardiovascular risk factors, pre-existing cardiovascular conditions and older patients. In addition, the outcomes these patients face are disproportionately more severe. Second, SARS-CoV-2 infection can be complicated by life-threatening acute cardiovascular diseases. Despite the rapid ongoing evolution of information about this pandemic, this review aims to highlight cardiovascular pathologies related to COVID-19 as either comorbidities, including concerns and uncertainty regarding the effect of renin-angiotensin-aldosterone system (RAAS) inhibitors on angiotensin conversion enzyme 2, or cardiovascular complications.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Comorbidade , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
20.
Zool Res ; 41(6): 621-631, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33045777

RESUMO

Understanding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clarifying antiviral immunity in hosts are critical aspects for the development of vaccines and antivirals. Mice are frequently used to generate animal models of infectious diseases due to their convenience and ability to undergo genetic manipulation. However, normal adult mice are not susceptible to SARS-CoV-2. Here, we developed a viral receptor (human angiotensin-converting enzyme 2, hACE2) pulmonary transfection mouse model to establish SARS-CoV-2 infection rapidly in the mouse lung. Based on the model, the virus successfully infected the mouse lung 2 days after transfection. Viral RNA/protein, innate immune cell infiltration, inflammatory cytokine expression, and pathological changes in the infected lungs were observed after infection. Further studies indicated that neutrophils were the first and most abundant leukocytes to infiltrate the infected lungs after viral infection. In addition, using infected CXCL5-knockout mice, chemokine CXCL5 was responsible for neutrophil recruitment. CXCL5 knockout decreased lung inflammation without diminishing viral clearance, suggesting a potential target for controlling pneumonia.


Assuntos
Betacoronavirus/imunologia , Quimiocina CXCL5/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/imunologia , Neutrófilos/imunologia , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Animais , Betacoronavirus/genética , Betacoronavirus/fisiologia , Linhagem Celular , Quimiocina CXCL5/genética , Quimiocina CXCL5/metabolismo , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/metabolismo , Neutrófilos/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/virologia
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