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1.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33384338

RESUMO

Human adenovirus species D (HAdV-D) types are currently being explored as vaccine vectors for coronavirus disease 2019 (COVID-19) and other severe infectious diseases. The efficacy of such vector-based vaccines depends on functional interactions with receptors on host cells. Adenoviruses of different species are assumed to enter host cells mainly by interactions between the knob domain of the protruding fiber capsid protein and cellular receptors. Using a cell-based receptor-screening assay, we identified CD46 as a receptor for HAdV-D56. The function of CD46 was validated in infection experiments using cells lacking and overexpressing CD46, and by competition infection experiments using soluble CD46. Remarkably, unlike HAdV-B types that engage CD46 through interactions with the knob domain of the fiber protein, HAdV-D types infect host cells through a direct interaction between CD46 and the hexon protein. Soluble hexon proteins (but not fiber knob) inhibited HAdV-D56 infection, and surface plasmon analyses demonstrated that CD46 binds to HAdV-D hexon (but not fiber knob) proteins. Cryoelectron microscopy analysis of the HAdV-D56 virion-CD46 complex confirmed the interaction and showed that CD46 binds to the central cavity of hexon trimers. Finally, soluble CD46 inhibited infection by 16 out of 17 investigated HAdV-D types, suggesting that CD46 is an important receptor for a large group of adenoviruses. In conclusion, this study identifies a noncanonical entry mechanism used by human adenoviruses, which adds to the knowledge of adenovirus biology and can also be useful for development of adenovirus-based vaccine vectors.


Assuntos
Adenovírus Humanos , Proteínas do Capsídeo , Regulação Viral da Expressão Gênica , Internalização do Vírus , Adenovírus Humanos/genética , Adenovírus Humanos/metabolismo , /metabolismo , Proteínas do Capsídeo/biossíntese , Proteínas do Capsídeo/genética , Linhagem Celular , Humanos
2.
Elife ; 102021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393462

RESUMO

Coronavirus entry is mediated by the spike protein that binds the receptor and mediates fusion after cleavage by host proteases. The proteases that mediate entry differ between cell lines, and it is currently unclear which proteases are relevant in vivo. A remarkable feature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the presence of a multibasic cleavage site (MBCS), which is absent in the SARS-CoV spike. Here, we report that the SARS-CoV-2 spike MBCS increases infectivity on human airway organoids (hAOs). Compared with SARS-CoV, SARS-CoV-2 entered faster into Calu-3 cells and, more frequently, formed syncytia in hAOs. Moreover, the MBCS increased entry speed and plasma membrane serine protease usage relative to cathepsin-mediated endosomal entry. Blocking serine proteases, but not cathepsins, effectively inhibited SARS-CoV-2 entry and replication in hAOs. Our findings demonstrate that SARS-CoV-2 enters relevant airway cells using serine proteases, and suggest that the MBCS is an adaptation to this viral entry strategy.


Assuntos
Organoides/virologia , Sistema Respiratório/virologia , Glicoproteína da Espícula de Coronavírus/química , Internalização do Vírus , Motivos de Aminoácidos , Animais , Fusão Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Vírus da SARS/química , Vírus da SARS/fisiologia , Serina Endopeptidases , Células Vero
3.
Viruses ; 13(1)2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33418950

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), employs host-cell angiotensin-converting enzyme 2 (ACE2) for cell entry. Genetic analyses of ACE2 have identified several single-nucleotide polymorphisms (SNPs) specific to different human populations. Molecular dynamics simulations have indicated that several of these SNPs could affect interactions between SARS-CoV-2 and ACE2, thereby providing a partial explanation for the regional differences observed in SARS-CoV-2 infectivity and severity. However, the significance of population-specific ACE2 SNPs in SARS-CoV-2 infectivity is unknown, as no in vitro validation studies have been performed. Here, we analyzed the impact of eight SNPs found in specific populations on receptor binding and cell entry in vitro. Except for a SNP causing a nonsense mutation that reduced ACE2 expression, none of the selected SNPs markedly altered the interaction between ACE2 and the SARS-CoV-2 spike protein (SARS-2-S), which is responsible for receptor recognition and cell entry, or the efficiency of viral cell entry mediated by SARS-2-S. Our findings indicate that ACE2 polymorphisms have limited impact on the ACE2-dependent cell entry of SARS-CoV-2 and underscore the importance of future studies on the involvement of population-specific SNPs of other host genes in susceptibility toward SARS-CoV-2 infection.


Assuntos
/genética , /virologia , Receptores Virais/genética , /fisiologia , Substituição de Aminoácidos , Genética Populacional , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Mutagênese , Testes de Neutralização , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Receptores Virais/química , Internalização do Vírus
4.
Nat Commun ; 12(1): 250, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431856

RESUMO

Understanding the mechanism for antibody neutralization of SARS-CoV-2 is critical for the development of effective therapeutics and vaccines. We recently isolated a large number of monoclonal antibodies from SARS-CoV-2 infected individuals. Here we select the top three most potent yet variable neutralizing antibodies for in-depth structural and functional analyses. Crystal structural comparisons reveal differences in the angles of approach to the receptor binding domain (RBD), the size of the buried surface areas, and the key binding residues on the RBD of the viral spike glycoprotein. One antibody, P2C-1F11, most closely mimics binding of receptor ACE2, displays the most potent neutralizing activity in vitro and conferred strong protection against SARS-CoV-2 infection in Ad5-hACE2-sensitized mice. It also occupies the largest binding surface and demonstrates the highest binding affinity to RBD. More interestingly, P2C-1F11 triggers rapid and extensive shedding of S1 from the cell-surface expressed spike glycoprotein, with only minimal such effect by the remaining two antibodies. These results offer a structural and functional basis for potent neutralization via disruption of the very first and critical steps for SARS-CoV-2 cell entry.


Assuntos
/química , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/imunologia , /imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Sítios de Ligação , /virologia , Modelos Animais de Doenças , Epitopos , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Receptores Virais/imunologia , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
5.
Sci Rep ; 11(1): 413, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432067

RESUMO

The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of basigin. Finally, removing basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.


Assuntos
Basigina/metabolismo , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , /virologia , Linhagem Celular , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Ligação Proteica , Internalização do Vírus
6.
PLoS Pathog ; 17(1): e1009153, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33395426

RESUMO

Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae.


Assuntos
/imunologia , Neuropilina-1/imunologia , Internalização do Vírus , /patologia , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/virologia , Humanos , Memória Imunológica , Bulbo Olfatório/imunologia , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Linfócitos T/imunologia , Linfócitos T/patologia
7.
Cell Prolif ; 54(1): e12953, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33211371

RESUMO

OBJECTIVES: Using strategy of drug repurposing, antiviral agents against influenza A virus (IAV) and newly emerging SARS-coronavirus 2 (SARS-CoV-2, also as 2019-nCoV) could be quickly screened out. MATERIALS AND METHODS: A previously reported engineered replication-competent PR8 strain carrying luciferase reporter gene (IAV-luc) and multiple pseudotyped IAV and SARS-CoV-2 virus was used. To specifically evaluate the pH change of vesicles containing IAV, we constructed an A549 cell line with endosomal and lysosomal expression of pHluorin2. RESULTS: Here, we identified azithromycin (AZ) as an effective inhibitor against multiple IAV and SARS-CoV-2 strains. We found that AZ treatment could potently inhibit IAV infection in vitro. Moreover, using pseudotyped virus model, AZ could also markedly block the entry of SARS-CoV-2 in HEK293T-ACE2 and Caco2 cells. Mechanistic studies further revealed that such effect was independent of interferon signalling. AZ treatment neither impaired the binding and internalization of IAV virions, nor the viral replication, but rather inhibited the fusion between viral and vacuolar membranes. Using a NPC1-pHluorin2 reporter cell line, we confirmed that AZ treatment could alkalize the vesicles containing IAV virions, thereby preventing pH-dependent membrane fusion. CONCLUSIONS: Overall, our findings demonstrate that AZ can exert broad-spectrum antiviral effects against IAV and SARS-CoV-2, and could be served as a potential clinical anti-SARS-CoV-2 drug in emergency as well as a promising lead compound for the development of next-generation anti-IAV drugs.


Assuntos
Antivirais/farmacologia , Azitromicina/farmacologia , Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Internalização do Vírus/efeitos dos fármacos , Células A549 , /genética , Células CACO-2 , Células HEK293 , Células HeLa , Humanos , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/genética , Interferons/genética , Interferons/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
9.
Cell ; 184(1): 76-91.e13, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33147444

RESUMO

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.


Assuntos
Infecções por Coronavirus/genética , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , /fisiologia , /metabolismo , Animais , /virologia , Linhagem Celular , Chlorocebus aethiops , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Coronavirus/classificação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Técnicas de Inativação de Genes , Redes Reguladoras de Genes , Células HEK293 , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Células Vero , Internalização do Vírus
10.
Cell ; 184(1): 106-119.e14, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33333024

RESUMO

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.


Assuntos
/genética , Infecções por Coronavirus/genética , Coronavirus/fisiologia , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , /fisiologia , Células A549 , Animais , Vias Biossintéticas/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Colesterol/biossíntese , Colesterol/metabolismo , Análise por Conglomerados , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Resfriado Comum/genética , Resfriado Comum/virologia , Coronavirus/classificação , Infecções por Coronavirus/virologia , Técnicas de Inativação de Genes , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Camundongos , Fosfatidilinositóis/biossíntese , Células Vero , Internalização do Vírus/efeitos dos fármacos , Replicação Viral
11.
J Med Virol ; 93(2): 863-869, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32691890

RESUMO

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.


Assuntos
/genética , Furina/genética , Esclerose Múltipla/genética , Receptores Virais/genética , Serina Endopeptidases/genética , /metabolismo , /virologia , Estudos de Coortes , Furina/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Humanos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/virologia , Polimorfismo Genético , Ligação Proteica , Receptores Virais/metabolismo , /metabolismo , Serina Endopeptidases/metabolismo , Espanha , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Inquéritos e Questionários , Internalização do Vírus , Sequenciamento Completo do Exoma
12.
Physiol Rep ; 8(24): e14649, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33369281

RESUMO

Discovering therapeutics for COVID-19 is a priority. Besides high-throughput screening of compounds, candidates might be identified based on their known mechanisms of action and current understanding of the SARs-CoV-2 life cycle. Using this approach, proton pump (PPIs) and sodium-hydrogen exchanger inhibitors (NHEIs) emerged, because of their potential to inhibit the release of extracellular vesicles (EVs; exosomes and/or microvesicles) that could promote disease progression, and to directly disrupt SARs-CoV-2 pathogenesis. If EVs exacerbate SARs-CoV-2 infection as suggested for other viruses, then inhibiting EV release by PPIs/NHEIs should be beneficial. Mechanisms underlying inhibition of EV release by these drugs remain uncertain, but may involve perturbing endosomal pH especially of multivesicular bodies where intraluminal vesicles (nascent exosomes) are formed. Additionally, PPIs might inhibit the endosomal sorting complex for transport machinery involved in EV biogenesis. Through perturbing endocytic vesicle pH, PPIs/NHEIs could also impede cleavage of SARs-CoV-2 spike protein by cathepsins necessary for viral fusion with the endosomal membrane. Although pulmonary epithelial cells may rely mainly on plasma membrane serine protease TMPRSS2 for cell entry, PPIs/NHEIs might be efficacious in ACE2-expressing cells where viral endocytosis is the major or a contributing entry pathway. These pharmaceutics might also perturb pH in the endoplasmic reticulum-Golgi intermediate and Golgi compartments, thereby potentially disrupting viral assembly and glycosylation of spike protein/ACE2, respectively. A caveat, however, is that facilitation not inhibition of avian infectious bronchitis CoV pathogenesis was reported in one study after increasing Golgi pH. Envelope protein-derived viroporins contributed to pulmonary edema formation in mice infected with SARs-CoV. If similar pathogenesis occurs with SARs-CoV-2, then blocking these channels with NHEIs could ameliorate disease pathogenesis. To ascertain their potential efficacy, PPIs/NHEIs need evaluation in cell and animal models at various phases of SARs-CoV-2 infection. If they prove to be therapeutic, the greatest benefit might be realized with the administration before the onset of severe cytokine release syndrome.


Assuntos
/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Bombas de Próton/metabolismo , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Internalização do Vírus , Animais , Humanos , Inibidores da Bomba de Prótons/farmacologia , /fisiologia , Trocadores de Sódio-Hidrogênio/metabolismo
14.
Gastroenterology ; 160(1): 39-46, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130103

RESUMO

The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.


Assuntos
/metabolismo , Gastroenterite/enzimologia , Microbioma Gastrointestinal , Mucosa Intestinal/enzimologia , Receptores Virais/metabolismo , /patogenicidade , /uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , /microbiologia , Fezes/microbiologia , Fezes/virologia , Gastroenterite/tratamento farmacológico , Gastroenterite/microbiologia , Gastroenterite/virologia , Microbioma Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/virologia , Sistema Renina-Angiotensina , Internalização do Vírus
15.
Curr Opin Allergy Clin Immunol ; 21(1): 8-15, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164997

RESUMO

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly become a great public health hazard globally. Nasal epithelial cells are an important site for SARS-CoV-2 infection and replication. The purpose of this review is to summarize recent findings on the endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) and the potential impact of SARS-CoV-2 infection. RECENT FINDINGS: Endotypes of CRSwNP are characterized by type 1, type 2 and type 3 inflammation according to patterns of inflammatory cells and the cytokines expressed in nasal tissue. Nasal epithelial cells show the highest expression of angiotensin-converting enzyme 2 (ACE2), the receptor for attachment and entry of SARS-CoV-2 into host cells, among all investigated cells in the respiratory tree. SARS-CoV-2 infection likely leads to increased activation of T-helper-1 (Th1) cell responses. Recent studies further suggest that ACE2 may be upregulated by type 1 and downregulated by type 2 inflammatory cytokines in nasal epithelial cells. SUMMARY: Expression of ACE2 in nasal epithelial cells is influenced by inflammatory endotypes of CRSwNP. Type 1 inflammation in nasal tissue may increase the risk of SARS-CoV-2 infection by upregulating ACE2 expression. However, clinical association between CRSwNP and COVID-19 is still unclear.


Assuntos
/epidemiologia , Pólipos Nasais/epidemiologia , Rinite/epidemiologia , Sinusite/epidemiologia , /metabolismo , /virologia , Comorbidade , Células Caliciformes/imunologia , Humanos , Inflamação/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Fatores de Risco , Sinusite/imunologia , Internalização do Vírus
16.
Curr Opin Allergy Clin Immunol ; 21(1): 1-7, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186186

RESUMO

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), a respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus), is a pandemic in over 120 countries worldwide. Risk factors for severe COVID-19 include older age, ethnicity, sex, comorbidities, and living conditions. Although asthmatics and those with allergies are susceptible to more severe outcomes to viral infections, interestingly, asthma has not been reported to be a major comorbidity of COVID-19. However, there are some conflicting reports on the impact of asthma on COVID-19. The underlying immunological and molecular mechanisms may explain at least in part these observations. Furthermore, environmental factors like air pollution that have detrimental effects on asthma and respiratory illnesses also have an impact on COVID-19. RECENT FINDINGS: Angiotensin-converting enzyme 2 (ACE2) is the receptor for the attachment and entry of SARS-CoV-2 into the host cells that is upregulated by Th1-mediated responses. In asthmatics, ACE2 gene expression is generally reduced and recent studies have shown a negative correlation between the levels of Th2 cytokines including IL-4, IL-5, and IL-13 in airway epithelial cells and other type 2 biomarkers with ACE2 expression. This may explain in part the potential protective role of asthma on COVID-19. Here, we review the relation of respiratory viral illnesses and asthma, the immune-molecular mechanisms of SARS-CoV-2 infection, the impact of asthma on COVID-19 and that of SARS-CoV-2 on asthma and allergic rhinitis, and the impact of environmental factors like air pollution on COVID-19. SUMMARY: Expression of ACE2 in airway epithelial cells in SARS-COV-2 is influenced by inflammatory profile. Respiratory allergic diseases like asthma appear to have a protective effect against SARS-COV-2 infection. However, the clinical association between asthma and SARS-COV-2 is not fully established and the underlying immune-molecular mechanisms may explain these observations.


Assuntos
Poluição do Ar/efeitos adversos , Asma/epidemiologia , Asma/imunologia , /imunologia , Pandemias , Rinite Alérgica/epidemiologia , Rinite Alérgica/imunologia , /fisiologia , /genética , /virologia , Comorbidade , Citocinas/metabolismo , Humanos , Fatores de Risco , Células Th1/imunologia , Internalização do Vírus
17.
Biochem Pharmacol ; 183: 114296, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33191206

RESUMO

The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Reposicionamento de Medicamentos/métodos , /efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Antivirais/química , Antivirais/farmacologia , Reposicionamento de Medicamentos/tendências , Humanos , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
18.
Med Res Rev ; 41(1): 72-135, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32852058

RESUMO

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three ß-coronaviruses have crossed the species barrier to infect humans: severe-acute respiratory syndrome (SARS)-CoV-1, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2 (2019-nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS-CoV-1, MERS-CoV, SARS-CoV-2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host-receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA-dependent RNA polymerase for viral RNA replication.


Assuntos
/epidemiologia , Química Farmacêutica , Surtos de Doenças , Antivirais/química , Antivirais/farmacologia , Reposicionamento de Medicamentos , Humanos , Internalização do Vírus/efeitos dos fármacos
20.
Antiviral Res ; 185: 104996, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309540

RESUMO

Middle East Respiratory Syndrome (MERS) is a respiratory disease caused by a coronavirus (MERS-CoV). Since its emergence in 2012, nosocomial amplifications have led to its high epidemic potential and mortality rate of 34.5%. To date, there is an unmet need for vaccines and specific therapeutics for this disease. Available treatments are either supportive medications in use for other diseases or those lacking specificity requiring higher doses. The viral infection mode is initiated by the attachment of the viral spike glycoprotein to the human Dipeptidyl Peptidase IV (DPP4). Our attempts to screen antivirals against MERS led us to identify montelukast sodium hydrate (MSH), an FDA-approved anti-asthma drug, as an agent attenuating MERS-CoV infection. We showed that MSH directly binds to MERS-CoV-Receptor-Binding Domain (RBD) and inhibits its molecular interaction with DPP4 in a dose-dependent manner. Our cell-based inhibition assays using MERS pseudovirions demonstrated that viral infection was significantly inhibited by MSH and was further validated using infectious MERS-CoV culture. Thus, we propose MSH as a potential candidate for therapeutic developments against MERS-CoV infections.


Assuntos
Acetatos/farmacologia , Antivirais/farmacologia , Ciclopropanos/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinolinas/farmacologia , Sulfetos/farmacologia , Animais , Antiasmáticos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Indutores do Citocromo P-450 CYP1A2/farmacologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Reposicionamento de Medicamentos , Células HEK293 , Humanos , Antagonistas de Leucotrienos/farmacologia , Receptores Virais/genética , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus/efeitos dos fármacos
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