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1.
PLoS One ; 16(2): e0246150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33534852

RESUMO

A coronavirus pandemic caused by a novel coronavirus (SARS-CoV-2) has spread rapidly worldwide since December 2019. Improved understanding and new strategies to cope with novel coronaviruses are urgently needed. Viruses (especially RNA viruses) encode a limited number and size (length of polypeptide chain) of viral proteins and must interact with the host cell components to control (hijack) the host cell machinery. To achieve this goal, the extensive mimicry of SLiMs in host proteins provides an effective strategy. However, little is known regarding SLiMs in coronavirus proteins and their potential targets in host cells. The objective of this study is to uncover SLiMs in coronavirus proteins that are present within host cells. These SLiMs have a high possibility of interacting with host intracellular proteins and hijacking the host cell machinery for virus replication and dissemination. In total, 1,479 SLiM hits were identified in the 16 proteins of 590 coronaviruses infecting humans. Overall, 106 host proteins were identified that may interact with SLiMs in 16 coronavirus proteins. These SLiM-interacting proteins are composed of many intracellular key regulators, such as receptors, transcription factors and kinases, and may have important contributions to virus replication, immune evasion and viral pathogenesis. A total of 209 pathways containing proteins that may interact with SLiMs in coronavirus proteins were identified. This study uncovers potential mechanisms by which coronaviruses hijack the host cell machinery. These results provide potential therapeutic targets for viral infections.


Assuntos
Infecções por Coronavirus/patologia , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Vírus da SARS/metabolismo , Proteínas Virais/metabolismo , Motivos de Aminoácidos , Infecções por Coronavirus/virologia , Bases de Dados de Proteínas , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Filogenia , Domínios e Motivos de Interação entre Proteínas , Proteínas/química , Proteínas/classificação , Vírus da SARS/isolamento & purificação , Transdução de Sinais/genética , Interface Usuário-Computador , Proteínas Virais/química , Proteínas Virais/classificação
2.
FASEB J ; 35(2): e21245, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495994

RESUMO

Lymphopenia is commonly observed in SARS and COVID-19 patients although the lymphocyte count is not always below 0.8 × 109 /L in all the patients. It is suggested that lymphopenia serves as a useful predictor for prognosis in the patients. It is also hypothesized that lymphopenia is related to glucocorticoids and apoptosis. However, the ordering between lymphopenia and apoptosis appears different between SARS and COVID-19 patients, ie, lymphopenia is prior to apoptosis in SARS patients whereas apoptosis is prior to lymphopenia in COVID-19 patients. This paper attempts to figure out this contradiction through three players, lymphopenia, glucocorticoids, and apoptosis. Although the literature does not provide a solid explanation, the level of glucocorticoids could determine the ordering between lymphopenia and apoptosis because the administration of high doses of glucocorticoids could lead to lymphopenia whereas low doses of glucocorticoids could benefit patients. In the meantime, this paper raises several questions, which need to be answered in order to better understand the whole course of COVID-19.


Assuntos
Glucocorticoides , Linfopenia , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave , Apoptose/efeitos dos fármacos , /tratamento farmacológico , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Linfopenia/tratamento farmacológico , Linfopenia/etiologia , Linfopenia/metabolismo , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/metabolismo
3.
Med Sci Monit ; 26: e928572, 2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33311429

RESUMO

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the third (following SARS-CoV and Middle East Respiratory Syndrome-CoV) zoonotic coronavirus that has crossed the species barrier in the 21st century, resulting in the development of serious human infection. The punishing effect of the recent outbreak of pandemic disease termed COVID-19 (coronavirus disease-19) caused by SARS-CoV-2 impelled us to gather the facts about the nature of coronaviruses. First, we introduce the basic information about coronavirus taxonomy, structure, and replication process to create the basis for more advanced consideration. In the following part of this review, we focused on interactions between the virus and the receptor on the host cell, as this stage is the critical process determining the species and tissue tropism, as well as clinical course of infection. We also illuminate the molecular basis of the strategy used by coronaviruses to cross the species barrier. We give special attention to the cellular receptor's interaction with S protein of different CoVs (dipeptidyl peptidase IV and angiotensin-converting enzyme 2), as well as the cellular proteases involved in proteolysis of this protein. These factors determine the virus entry and replication; thus, even fine quantitative or qualitative differences in their expression may crucially affect outcomes of infection. Understanding virus biology and characterization of the host factors involved in coronavirus transmission and pathogenesis may offer novel options for development of efficient therapeutic and preventive strategies.


Assuntos
/metabolismo , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/metabolismo , Interações Hospedeiro-Patógeno , Glicoproteína da Espícula de Coronavírus/metabolismo , Zoonoses/virologia , Animais , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/transmissão , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias/prevenção & controle , Vírus da SARS/metabolismo , Vírus da SARS/patogenicidade , /patogenicidade , Especificidade da Espécie , Internalização do Vírus , Replicação Viral , Zoonoses/epidemiologia , Zoonoses/patologia
4.
Emerg Microbes Infect ; 9(1): 2433-2445, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33073694

RESUMO

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1-3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.


Assuntos
Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/genética , Pneumonia Viral/patologia , Vírus da SARS/crescimento & desenvolvimento , Replicação Viral/genética , Células A549 , Adenoviridae/genética , Animais , Betacoronavirus/metabolismo , Linhagem Celular , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pandemias , Vírus da SARS/metabolismo , Células Vero , Ligação Viral
5.
Trends Immunol ; 41(11): 1006-1022, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33041212

RESUMO

The 2019 coronavirus pandemic remains a major public health concern. Neutralizing antibodies (nAbs) represent a cutting-edge antiviral strategy. We focus here on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, and discuss current progress in antibody research against rampant SARS-CoV-2 infections. We provide a perspective on the mechanisms of SARS-CoV-2-derived nAbs, comparing these with existing SARS-CoV-derived antibodies. We offer insight into how these antibodies cross-react and cross-neutralize by analyzing available structures of spike (S) glycoprotein-antibody complexes. We also propose ways of adopting antibody-based strategies - such as cocktail antibody therapeutics against SARS-CoV-2 - to overcome the possible resistance of currently identified mutants and mitigate possible antibody-dependent enhancement (ADE) pathologies. This review provides a platform for the progression of antibody and vaccine design against SARS-CoV-2, and possibly against future coronavirus pandemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vírus da SARS/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Ligação Proteica , Vírus da SARS/metabolismo , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
6.
Sci Rep ; 10(1): 16862, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033344

RESUMO

The prevalence of a novel ß-coronavirus (SARS-CoV-2) was declared as a public health emergency of international concern on 30 January 2020 and a global pandemic on 11 March 2020 by WHO. The spike glycoprotein of SARS-CoV-2 is regarded as a key target for the development of vaccines and therapeutic antibodies. In order to develop anti-viral therapeutics for SARS-CoV-2, it is crucial to find amino acid pairs that strongly attract each other at the interface of the spike glycoprotein and the human angiotensin-converting enzyme 2 (hACE2) complex. In order to find hot spot residues, the strongly attracting amino acid pairs at the protein-protein interaction (PPI) interface, we introduce a reliable inter-residue interaction energy calculation method, FMO-DFTB3/D/PCM/3D-SPIEs. In addition to the SARS-CoV-2 spike glycoprotein/hACE2 complex, the hot spot residues of SARS-CoV-1 spike glycoprotein/hACE2 complex, SARS-CoV-1 spike glycoprotein/antibody complex, and HCoV-NL63 spike glycoprotein/hACE2 complex were obtained using the same FMO method. Following this, a 3D-SPIEs-based interaction map was constructed with hot spot residues for the hACE2/SARS-CoV-1 spike glycoprotein, hACE2/HCoV-NL63 spike glycoprotein, and hACE2/SARS-CoV-2 spike glycoprotein complexes. Finally, the three 3D-SPIEs-based interaction maps were combined and analyzed to find the consensus hot spots among the three complexes. As a result of the analysis, two hot spots were identified between hACE2 and the three spike proteins. In particular, E37, K353, G354, and D355 of the hACE2 receptor strongly interact with the spike proteins of coronaviruses. The 3D-SPIEs-based map would provide valuable information to develop anti-viral therapeutics that inhibit PPIs between the spike protein of SARS-CoV-2 and hACE2.


Assuntos
Betacoronavirus/metabolismo , Biologia Computacional/métodos , Infecções por Coronavirus/epidemiologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Mapas de Interação de Proteínas , Glicoproteína da Espícula de Coronavírus/metabolismo , Anticorpos Antivirais/metabolismo , Sítios de Ligação , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/metabolismo , Humanos , Pandemias , Pneumonia Viral/virologia , Prevalência , Domínios Proteicos , Receptores Virais/metabolismo , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/virologia
7.
Viruses ; 12(10)2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003587

RESUMO

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is responsible for the current global coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The viral entry of SARS-CoV-2 depends on an interaction between the receptor-binding domain of its trimeric spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor. A better understanding of the spike/ACE2 interaction is still required to design anti-SARS-CoV-2 therapeutics. Here, we investigated the degree of cooperativity of ACE2 within both the SARS-CoV-2 and the closely related SARS-CoV-1 membrane-bound S glycoproteins. We show that there exist differential inter-protomer conformational transitions between both spike trimers. Interestingly, the SARS-CoV-2 spike exhibits a positive cooperativity for monomeric soluble ACE2 binding when compared to the SARS-CoV-1 spike, which might have more structural restraints. Our findings can be of importance in the development of therapeutics that block the spike/ACE2 interaction.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/metabolismo , Proteínas de Transporte , Infecções por Coronavirus/virologia , Microscopia Crioeletrônica , Células HEK293 , Humanos , Pandemias , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Internalização do Vírus
8.
Molecules ; 25(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867349

RESUMO

Three types of new coronaviruses (CoVs) have been identified recently as the causative viruses for the severe pneumonia-like respiratory illnesses, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and corona-virus disease 2019 (COVID-19). Neither therapeutic agents nor vaccines have been developed to date, which is a major drawback in controlling the present global pandemic of COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) and has resulted in more than 20,439,814 cases and 744,385 deaths. Each of the 3C-like (3CL) proteases of the three CoVs is essential for the proliferation of the CoVs, and an inhibitor of the 3CL protease (3CLpro) is thought to be an ideal therapeutic agent against SARS, MERS, or COVID-19. Among these, SARS-CoV is the first corona-virus isolated and has been studied in detail since the first pandemic in 2003. This article briefly reviews a series of studies on SARS-CoV, focusing on the development of inhibitors for the SARS-CoV 3CLpro based on molecular interactions with the 3CL protease. Our recent approach, based on the structure-based rational design of a novel scaffold for SARS-CoV 3CLpro inhibitor, is also included. The achievements summarized in this short review would be useful for the design of a variety of novel inhibitors for corona-viruses, including SARS-CoV-2.


Assuntos
Antivirais/química , Betacoronavirus/química , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Inibidores de Proteases/química , Vírus da SARS/patogenicidade , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/classificação , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Domínio Catalítico , Infecções por Coronavirus/tratamento farmacológico , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Humanos , Cinética , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/classificação , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/genética , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Especificidade por Substrato , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
9.
Eur Rev Med Pharmacol Sci ; 24(14): 7834-7844, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744711

RESUMO

The pandemic threat of COVID-19 causes serious concern for people and world organizations. The effect of Coronavirus disease on the lifestyle and economic status of humans is undeniable, and all of the researchers (biologists, pharmacists, physicians, and chemists) can help decrease its destructive effects. The molecular docking approach can provide a fast prediction of the positive influence the targets on the COVID-19 outbreak. In this work, we choose resveratrol (RV) derivatives (22 cases) and two newly released coordinate structures for COVID-19 as receptors [Papain-like Protease of SARS CoV-2 (PBD ID: 6W9C) and 2019-nCoV RNA-dependent RNA Polymerase (PBD ID: 6M71)]. The results show that conformational isomerism is significant and useful parameter for docking results. A wide spectrum of interactions such as Van der Waals, conventional hydrogen bond, Pi-donor hydrogen bond, Pi-Cation, Pi-sigma, Pi-Pi stacked, Amide-Pi stacked and Pi-Alkyl is detected via docking of RV derivatives and COVID-19 receptors. The potential inhibition effect of RV-13 (-184.99 kj/mol), and RV-12 (-173.76 kj/mol) is achieved at maximum value for 6W9C and 6M71, respectively.


Assuntos
Antivirais/metabolismo , Betacoronavirus/metabolismo , Papaína/metabolismo , Resveratrol/metabolismo , Vírus da SARS/metabolismo , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cristalografia por Raios X , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Pandemias , Papaína/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Estrutura Terciária de Proteína , Resveratrol/química , Resveratrol/uso terapêutico , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Proteínas não Estruturais Virais/química
10.
J Chem Inf Model ; 60(10): 5255-5264, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-32846088

RESUMO

The surface of proteins is vital in determining protein functions. Herein, a program, Protein Surface Printer (PSP), is built that performs multiple functions in quantifying protein surface domains. Two proteins, PETase and cytochrome P450, are used to validate that the program supports atomistic simulations with different combinations of programs and force fields. A case study is conducted on the structural analysis of the spike proteins of SARS-CoV-2 and SARS-CoV and the human cell receptor ACE2. Although the surface domains of both spike proteins are highly similar, their receptor-binding domains (RBDs) and the O-linked glycan domains are structurally different. The O-linked glycan domain of SARS-CoV-2 is highly positively charged, which may promote binding to negatively charged human cells.


Assuntos
Betacoronavirus/metabolismo , Peptidil Dipeptidase A/metabolismo , Vírus da SARS/metabolismo , Software , Glicoproteína da Espícula de Coronavírus/metabolismo , Betacoronavirus/química , Betacoronavirus/fisiologia , Sítios de Ligação , Infecções por Coronavirus/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/metabolismo , Ligação Proteica , Domínios Proteicos , Vírus da SARS/química , Vírus da SARS/fisiologia , Síndrome Respiratória Aguda Grave/metabolismo , Glicoproteína da Espícula de Coronavírus/química
11.
Protein Sci ; 29(10): 2038-2042, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32822073

RESUMO

The Envelope protein (E) is one of the four structural proteins encoded by the genome of SARS-CoV and SARS-CoV-2 Coronaviruses. It is an integral membrane protein, highly expressed in the host cell, which is known to have an important role in Coronaviruses maturation, assembly and virulence. The E protein presents a PDZ-binding motif at its C-terminus. One of the key interactors of the E protein in the intracellular environment is the PDZ containing protein PALS1. This interaction is known to play a key role in the SARS-CoV pathology and suspected to affect the integrity of the lung epithelia. In this paper we measured and compared the affinity of peptides mimicking the E protein from SARS-CoV and SARS-CoV-2 for the PDZ domain of PALS1, through equilibrium and kinetic binding experiments. Our results support the hypothesis that the increased virulence of SARS-CoV-2 compared to SARS-CoV may rely on the increased affinity of its Envelope protein for PALS1.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Proteínas de Membrana/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Pneumonia Viral/metabolismo , Vírus da SARS/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Proteínas do Envelope Viral/metabolismo , Sequência de Aminoácidos , Betacoronavirus/química , Sítios de Ligação , Infecções por Coronavirus/virologia , Humanos , Proteínas de Membrana/química , Modelos Moleculares , Núcleosídeo-Fosfato Quinase/química , Domínios PDZ , Pandemias , Peptídeos/química , Peptídeos/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Vírus da SARS/química , Síndrome Respiratória Aguda Grave/virologia , Proteínas do Envelope Viral/química
13.
Sci Rep ; 10(1): 12493, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719454

RESUMO

The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (Mpro). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 Mpro. However, the mechanism of action of SARS-CoV-2 Mpro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 Mpro and three drug candidates by performing pharmacophore modeling and 1 µs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 Mpro.


Assuntos
Betacoronavirus/metabolismo , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Betacoronavirus/química , Betacoronavirus/isolamento & purificação , Sítios de Ligação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Desenho de Fármacos , Humanos , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Inibidores de Proteases/metabolismo , Estrutura Terciária de Proteína , Vírus da SARS/química , Vírus da SARS/isolamento & purificação , Vírus da SARS/metabolismo , Alinhamento de Sequência , Proteínas não Estruturais Virais/metabolismo
14.
Wiley Interdiscip Rev RNA ; 11(5): e1614, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32638509

RESUMO

Coronaviruses, including SARS-Cov-2, are RNA-based pathogens that interface with a large variety of RNA-related cellular processes during infection. These processes include capping, polyadenylation, localization, RNA stability, translation, and regulation by RNA binding proteins or noncoding RNA effectors. The goal of this article is to provide an in-depth perspective on the current state of knowledge of how various coronaviruses interact with, usurp, and/or avoid aspects of these cellular RNA biology machineries. A thorough understanding of how coronaviruses interact with RNA-related posttranscriptional processes in the cell should allow for new insights into aspects of viral pathogenesis as well as identify new potential avenues for the development of anti-coronaviral therapeutics. This article is categorized under: RNA in Disease and Development > RNA in Disease.


Assuntos
Betacoronavirus/genética , Interações Hospedeiro-Patógeno/genética , MicroRNAs/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Viral/genética , Animais , Betacoronavirus/metabolismo , Humanos , MicroRNAs/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Poliadenilação , Biossíntese de Proteínas , Edição de RNA , Processamento de RNA , Estabilidade de RNA , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Vírus da SARS/genética , Vírus da SARS/metabolismo
15.
Virol Sin ; 35(3): 311-320, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32602046

RESUMO

The mechanism of how SARS-CoV-2 causes severe multi-organ failure is largely unknown. Acute kidney injury (AKI) is one of the frequent organ damage in severe COVID-19 patients. Previous studies have shown that human renal tubule cells could be the potential host cells targeted by SARS-CoV-2. Traditional cancer cell lines or immortalized cell lines are genetically and phenotypically different from host cells. Animal models are widely used, but often fail to reflect a physiological and pathogenic status because of species tropisms. There is an unmet need for normal human epithelial cells for disease modeling. In this study, we successfully established long term cultures of normal human kidney proximal tubule epithelial cells (KPTECs) in 2D and 3D culture systems using conditional reprogramming (CR) and organoids techniques. These cells had the ability to differentiate and repair DNA damage, and showed no transforming property. Importantly, the CR KPTECs maintained lineage function with expression of specific transporters (SLC34A3 and cubilin). They also expressed angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV and SARS-CoV-2. In contrast, cancer cell line did not express endogenous SLC34A3, cubilin and ACE2. Very interestingly, ACE2 expression was around twofold higher in 3D organoids culture compared to that in 2D CR culture condition. Pseudovirion assays demonstrated that SARS-CoV spike (S) protein was able to enter CR cells with luciferase reporter. This integrated 2D CR and 3D organoid cultures provide a physiological ex vivo model to study kidney functions, innate immune response of kidney cells to viruses, and a novel platform for drug discovery and safety evaluation.


Assuntos
Betacoronavirus/metabolismo , Técnicas de Cultura de Células/métodos , Infecções por Coronavirus/virologia , Coronavirus/metabolismo , Células Epiteliais/virologia , Rim/virologia , Pneumonia Viral/virologia , Animais , Betacoronavirus/patogenicidade , Linhagem Celular , Coronavirus/patogenicidade , Dano ao DNA , Modelos Animais de Doenças , Humanos , Organoides , Pandemias , Peptidil Dipeptidase A/metabolismo , Receptores de Superfície Celular/metabolismo , Vírus da SARS/metabolismo , Vírus da SARS/patogenicidade , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo
16.
Chaos ; 30(6): 061102, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32611087

RESUMO

There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mpro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 Mpro is 1900% more sensitive than SARS CoV-1 Mpro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mpro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.


Assuntos
Betacoronavirus/metabolismo , Domínio Catalítico/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/metabolismo , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/metabolismo , Sequência de Aminoácidos , Sítios de Ligação/efeitos dos fármacos , Cristalografia por Raios X , Cisteína Endopeptidases/efeitos dos fármacos , Desenho de Fármacos , Humanos , Pandemias , Vírus da SARS/metabolismo , Proteínas não Estruturais Virais/efeitos dos fármacos
17.
Infect Genet Evol ; 84: 104440, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32622082

RESUMO

SARS-CoV-2, a new coronavirus strain responsible for COVID-19, has emerged in Wuhan City, China, and continuing its global pandemic nature. The availability of the complete gene sequences of the virus helps to know about the origin and molecular characteristics of this virus. In the present study, we performed bioinformatic analysis of the available gene sequence data of SARS-CoV-2 for the understanding of evolution and molecular characteristics and immunogenic resemblance of the circulating viruses. Phylogenetic analysis was performed for four types of representative viral proteins (spike, membrane, envelope and nucleoprotein) of SARS-CoV-2, HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HKU1, MERS-CoV, HKU4, HKU5 and BufCoV-HKU26. The findings demonstrated that SARS-CoV-2 exhibited convergent evolutionary relation with previously reported SARS-CoV. It was also depicted that SARS-CoV-2 proteins were highly similar and identical to SARS-CoV proteins, though proteins from other coronaviruses showed a lower level of resemblance. The cross-checked conservancy analysis of SARS-CoV-2 antigenic epitopes showed significant conservancy with antigenic epitopes derived from SARS-CoV. Descriptive epidemiological analysis on several epidemiological indices was performed on available epidemiological outbreak information from several open databases on COVID-19 (SARS-CoV-2). Satellite-derived imaging data have been employed to understand the role of temperature in the environmental persistence of the virus. Findings of the descriptive analysis were used to describe the global impact of newly emerged SARS-CoV-2, and the risk of an epidemic in Bangladesh.


Assuntos
Antígenos Virais/genética , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Genoma Viral , Pandemias , Pneumonia Viral/epidemiologia , Vírus da SARS/genética , Glicoproteína da Espícula de Coronavírus/química , Alphacoronavirus/classificação , Alphacoronavirus/genética , Alphacoronavirus/metabolismo , Sequência de Aminoácidos , Animais , Antígenos Virais/química , Antígenos Virais/metabolismo , Bangladesh/epidemiologia , Sequência de Bases , Betacoronavirus/classificação , Betacoronavirus/metabolismo , Sítios de Ligação , Quirópteros/virologia , Biologia Computacional , Coronavirus Humano 229E/classificação , Coronavirus Humano 229E/genética , Coronavirus Humano 229E/metabolismo , Infecções por Coronavirus/virologia , Coronavirus Humano NL63/classificação , Coronavirus Humano NL63/genética , Coronavirus Humano NL63/metabolismo , Coronavirus Humano OC43/classificação , Coronavirus Humano OC43/genética , Coronavirus Humano OC43/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/classificação , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Modelos Moleculares , Mutação , Nucleoproteínas/química , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Filogenia , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/classificação , Vírus da SARS/metabolismo , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
18.
J Mol Biol ; 432(19): 5212-5226, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32710986

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is a major concern in coronavirus disease 2019 (COVID-19) prevention and economic reopening. However, rigorous determination of SARS-CoV-2 infectivity is very difficult owing to its continuous evolution with over 10,000 single nucleotide polymorphisms (SNP) variants in many subtypes. We employ an algebraic topology-based machine learning model to quantitatively evaluate the binding free energy changes of SARS-CoV-2 spike glycoprotein (S protein) and host angiotensin-converting enzyme 2 receptor following mutations. We reveal that the SARS-CoV-2 virus becomes more infectious. Three out of six SARS-CoV-2 subtypes have become slightly more infectious, while the other three subtypes have significantly strengthened their infectivity. We also find that SARS-CoV-2 is slightly more infectious than SARS-CoV according to computed S protein-angiotensin-converting enzyme 2 binding free energy changes. Based on a systematic evaluation of all possible 3686 future mutations on the S protein receptor-binding domain, we show that most likely future mutations will make SARS-CoV-2 more infectious. Combining sequence alignment, probability analysis, and binding free energy calculation, we predict that a few residues on the receptor-binding motif, i.e., 452, 489, 500, 501, and 505, have high chances to mutate into significantly more infectious COVID-19 strains.


Assuntos
Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Evolução Molecular , Mutação , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Betacoronavirus/classificação , Análise por Conglomerados , Análise Mutacional de DNA , Genótipo , Mapeamento Geográfico , Humanos , Aprendizado de Máquina , Modelos Moleculares , Pandemias , Peptidil Dipeptidase A/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Probabilidade , Ligação Proteica/genética , Receptores Virais/metabolismo , Vírus da SARS/química , Vírus da SARS/genética , Vírus da SARS/metabolismo , Vírus da SARS/patogenicidade , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
19.
Infect Genet Evol ; 84: 104389, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32502733

RESUMO

The newly identified SARS-CoV-2 has now been reported from around 185 countries with more than a million confirmed human cases including more than 120,000 deaths. The genomes of SARS-COV-2 strains isolated from different parts of the world are now available and the unique features of constituent genes and proteins need to be explored to understand the biology of the virus. Spike glycoprotein is one of the major targets to be explored because of its role during the entry of coronaviruses into host cells. We analyzed 320 whole-genome sequences and 320 spike protein sequences of SARS-CoV-2 using multiple sequence alignment. In this study, 483 unique variations have been identified among the genomes of SARS-CoV-2 including 25 nonsynonymous mutations and one deletion in the spike (S) protein. Among the 26 variations detected in S, 12 variations were located at the N-terminal domain (NTD) and 6 variations at the receptor-binding domain (RBD) which might alter the interaction of S protein with the host receptor angiotensin-converting enzyme 2 (ACE2). Besides, 22 amino acid insertions were identified in the spike protein of SARS-CoV-2 in comparison with that of SARS-CoV. Phylogenetic analyses of spike protein revealed that Bat coronavirus have a close evolutionary relationship with circulating SARS-CoV-2. The genetic variation analysis data presented in this study can help a better understanding of SARS-CoV-2 pathogenesis. Based on results reported herein, potential inhibitors against S protein can be designed by considering these variations and their impact on protein structure.


Assuntos
Alphacoronavirus/genética , Betacoronavirus/genética , Genoma Viral , Peptidil Dipeptidase A/química , Vírus da SARS/genética , Glicoproteína da Espícula de Coronavírus/química , Alphacoronavirus/classificação , Alphacoronavirus/metabolismo , Animais , Sequência de Bases , Betacoronavirus/classificação , Betacoronavirus/metabolismo , Sítios de Ligação , Quirópteros/virologia , Expressão Gênica , Humanos , Modelos Moleculares , Mutação , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/classificação , Vírus da SARS/metabolismo , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Homologia Estrutural de Proteína , Ligação Viral
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