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1.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34479991

RESUMO

COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNß directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNß reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNß/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.


Assuntos
Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/virologia , Macrófagos/metabolismo , Animais , COVID-19/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais
2.
Cells ; 10(8)2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34440791

RESUMO

Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has instantaneously emerged as a worldwide pandemic. However, humans encountered other coronaviruses in the past, and they caused a broad range of symptoms, from mild to life-threatening, depending on the virus and immunocompetence of the host. Most human coronaviruses interact with the proteins and/or double-membrane vesicles of autophagy, the membrane trafficking pathway that degrades and recycles the intracellular protein aggregates, organelles, and pathogens, including viruses. However, coronaviruses often neutralize and hijack this pathway to complete their life cycle. In this review, we discuss the interactions of human coronaviruses and autophagy, including recent data from SARS-CoV-2-related studies. Some of these interactions (for example, viral block of the autophagosome-lysosome fusion), while being conserved across multiple coronaviruses, are accomplished via different molecular mechanisms. Therefore, it is important to understand the molecular interplay between human coronaviruses and autophagy for developing efficient therapies against coronaviral diseases.


Assuntos
Autofagia , Infecções por Coronavirus/fisiopatologia , Coronavirus/metabolismo , COVID-19/metabolismo , COVID-19/fisiopatologia , Infecções por Coronavirus/metabolismo , Humanos , Lisossomos , SARS-CoV-2/metabolismo
3.
Front Immunol ; 12: 708264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305949

RESUMO

There are still many unanswered questions concerning viral SARS-CoV-2 pathogenesis in COVID-19. Accessory proteins in SARS-CoV-2 consist of eleven viral proteins whose roles during infection are still not completely understood. Here, a review on the current knowledge of SARS-CoV-2 accessory proteins is summarized updating new research that could be critical in understanding SARS-CoV-2 interaction with the host. Some accessory proteins such as ORF3b, ORF6, ORF7a and ORF8 have been shown to be important IFN-I antagonists inducing an impairment in the host immune response. In addition, ORF3a is involved in apoptosis whereas others like ORF9b and ORF9c interact with cellular organelles leading to suppression of the antiviral response in infected cells. However, possible roles of ORF7b and ORF10 are still awaiting to be described. Also, ORF3d has been reassigned. Relevant information on the knowns and the unknowns in these proteins is analyzed, which could be crucial for further understanding of SARS-CoV-2 pathogenesis and to design strategies counteracting their actions evading immune responses in COVID-19.


Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Proteínas Virais Reguladoras e Acessórias/imunologia , COVID-19/patologia , Coronavirus/metabolismo , Coronavirus/patogenicidade , Humanos , Evasão da Resposta Imune , Imunidade , Interferons/antagonistas & inibidores , SARS-CoV-2/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
4.
J Chem Phys ; 154(24): 245101, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34241335

RESUMO

Ethanol is highly effective against various enveloped viruses and can disable the virus by disintegrating the protective envelope surrounding it. The interactions between the coronavirus envelope (E) protein and its membrane environment play key roles in the stability and function of the viral envelope. By using molecular dynamics simulation, we explore the underlying mechanism of ethanol-induced disruption of a model coronavirus membrane and, in detail, interactions of the E-protein and lipids. We model the membrane bilayer as N-palmitoyl-sphingomyelin and 1-palmitoyl-2-oleoylphosphatidylcholine lipids and the coronavirus E-protein. The study reveals that ethanol causes an increase in the lateral area of the bilayer along with thinning of the bilayer membrane and orientational disordering of lipid tails. Ethanol resides at the head-tail region of the membrane and enhances bilayer permeability. We found an envelope-protein-mediated increase in the ordering of lipid tails. Our simulations also provide important insights into the orientation of the envelope protein in a model membrane environment. At ∼25 mol. % of ethanol in the surrounding ethanol-water phase, we observe disintegration of the lipid bilayer and dislocation of the E-protein from the membrane environment.


Assuntos
Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Coronavirus/metabolismo , Desinfetantes/farmacologia , Etanol/farmacologia , Proteínas do Envelope Viral/metabolismo , Coronavirus/fisiologia , Bicamadas Lipídicas/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Permeabilidade
5.
Phys Chem Chem Phys ; 23(25): 13926-13933, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34137759

RESUMO

The global outbreak of the COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Bat virus RaTG13 and SARS-CoV are also members of the coronavirus family and SARS-CoV caused a world-wide pandemic in 2003. SARS-CoV-2, SARS-CoV and RaTG13 bind to angiotensin-converting enzyme 2 (ACE2) through their receptor-binding domain (RBD) of the spike protein. SARS-CoV-2 binds ACE2 with a higher binding affinity than SARS-CoV and RaTG13. Here we performed molecular dynamics simulation of these binding complexes and calculated their binding free energies using a computational alanine scanning method. Our MD simulation and hotspot residue analysis showed that the lower binding affinity of SARS-CoV to ACE2 vs. SARS-CoV-2 to ACE2 can be explained by different hotspot interactions in these two systems. We also found that the lower binding affinity of RaTG13 to ACE2 is mainly due to a mutated residue (D501) which resulted in a less favorable complex formation for binding. We also calculated an important mutation of N501Y in SARS-CoV-2 using both alanine scanning calculation and a thermodynamic integration (TI) method. Both calculations confirmed a significant increase of the binding affinity of the N501Y mutant to ACE2 and explained its molecular mechanism. The present work provides an important theoretical basis for understanding the molecular mechanism in coronavirus spike protein binding to human ACE2.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Quirópteros/virologia , Coronavirus/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Animais , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Vírus da SARS/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Termodinâmica
6.
Infect Genet Evol ; 93: 104944, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34052418

RESUMO

Since the emergence of their primitive strains, the complexity surrounding their pathogenesis, constant genetic mutation and translation are contributing factors to the scarcity of a successful vaccine for coronaviruses till moment. Although, the recent announcement of vaccine breakthrough for COVID-19 renews the hope, however, there remains a major challenge of accessibility to urgently match the rapid global therapeutic demand for curtailing the pandemic, thereby creating an impetus for further search. The reassessment of results from a stream of experiments is of enormous importance in identifying bona fide lead-like candidates to fulfil this quest. This review comprehensively highlights the common pathomechanisms and pharmacological targets of HCoV-OC43, SARS-CoV-1, MERS-CoV and SARS-CoV-2, and potent therapeutic potentials from basic and clinical experimental investigations. The implicated targets for the prevention and treatment include the viral proteases (Mpro, PLpro, 3CLpro), viral structural proteins (S- and N-proteins), non-structural proteins (nsp 3, 8, 10, 14, 16), accessory protein (ns12.9), viroporins (3a, E, 8a), enzymes (RdRp, TMPRSS2, ADP-ribosyltransferase, MTase, 2'-O-MTase, TATase, furin, cathepsin, deamidated human triosephosphate isomerase), kinases (MAPK, ERK, PI3K, mTOR, AKT, Abl2), interleukin-6 receptor (IL-6R) and the human host receptor, ACE2. Notably among the 109 overviewed inhibitors include quercetin, eriodictyol, baicalin, luteolin, melatonin, resveratrol and berberine from natural products, GC373, NP164 and HR2P-M2 from peptides, 5F9, m336 and MERS-GD27 from specific human antibodies, imatinib, remdesivir, ivermectin, chloroquine, hydroxychloroquine, nafamostat, interferon-ß and HCQ from repurposing libraries, some iron chelators and traditional medicines. This review represents a model for further translational studies for effective anti-CoV therapeutic designs.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/etiologia , Coronavirus/patogenicidade , Interações Hospedeiro-Patógeno , Antivirais/uso terapêutico , Coronavirus/efeitos dos fármacos , Coronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavirus Humano OC43/efeitos dos fármacos , Coronavirus Humano OC43/patogenicidade , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/metabolismo
7.
Viruses ; 13(4)2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33804957

RESUMO

Several life-threatening viruses have recently appeared, including the coronavirus, infecting a variety of human and animal hosts and causing a range of diseases like human upper respiratory tract infections. They not only cause serious human and animal deaths, but also cause serious public health problems worldwide. Currently, seven species are known to infect humans, namely SARS-CoV-2, MERS-CoV, SARS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1. The coronavirus nonstructural protein 16 (NSP16) structure is similar to the 5'-end capping system of mRNA used by eukaryotic hosts and plays a vital role in evading host immunity response and protects the nascent viral mRNA from degradation. NSP16 is also well-conserved among related coronaviruses and requires its binding partner NSP10 to activate its enzymatic activity. With the continued threat of viral emergence highlighted by human coronaviruses and SARS-CoV-2, mutant strains continue to appear, affecting the highly conserved NSP16: this provides a possible therapeutic approach applicable to any novel coronavirus. To this end, current information on the 2'-O-MTase activity mechanism, the differences between NSP16 and NSP10 in human coronaviruses, and the current potential prevention and treatment strategies related to NSP16 are summarized in this review.


Assuntos
Infecções por Coronavirus/virologia , Coronavirus/metabolismo , Metiltransferases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Animais , COVID-19/virologia , Coronavirus/enzimologia , Coronavirus/genética , Humanos , Metiltransferases/genética , SARS-CoV-2/enzimologia , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/genética
8.
Front Immunol ; 12: 573078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692778

RESUMO

Swine acute diarrhea syndrome coronavirus (SADS-CoV), first discovered in 2017, is a porcine enteric coronavirus that can cause acute diarrhea syndrome (SADS) in piglets. Here, we studied the role of SADS-CoV nucleocapsid (N) protein in innate immunity. Our results showed that SADS-CoV N protein could inhibit type I interferon (IFN) production mediated by Sendai virus (Sev) and could block the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3). Simultaneously, the IFN-ß promoter activity mediated by TANK binding kinase 1 (TBK1) or its upstream molecules in the RLRs signal pathway was inhibited by SADS-CoV N protein. Further investigations revealed that SADS-CoV N protein could counteract interaction between TNF receptor-associated factor 3 (TRAF3) and TBK1, which led to reduced TBK1 activation and IFN-ß production. Our study is the first report of the interaction between SADS-CoV N protein and the host antiviral innate immune responses, and the mechanism utilized by SADS-CoV N protein provides a new insight of coronaviruses evading host antiviral innate immunity.


Assuntos
Alphacoronavirus/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Interferon beta/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fator 3 Associado a Receptor de TNF/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alphacoronavirus/imunologia , Animais , Linhagem Celular , Coronavirus/imunologia , Coronavirus/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Quinase I-kappa B/imunologia , Quinase I-kappa B/metabolismo , Imunidade Inata , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/biossíntese , Interferon beta/imunologia , Interferon beta/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Suínos , Fator 3 Associado a Receptor de TNF/imunologia , Fator 3 Associado a Receptor de TNF/metabolismo
9.
J Phys Chem Lett ; 12(10): 2691-2698, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33689357

RESUMO

Severe acute respiratory syndrome coronaviruses have unusually large RNA genomes replicated by a multiprotein complex containing an RNA-dependent RNA polymerase (RdRp). Exonuclease activity enables the RdRp complex to remove wrongly incorporated bases via proofreading, a process not utilized by other RNA viruses. However, it is unclear why the RdRp complex needs proofreading and what the associated trade-offs are. Here we investigate the interplay among the accuracy, speed, and energetic cost of proofreading in the RdRp complex using a kinetic model and bioinformatics analysis. We find that proofreading nearly optimizes the rate of functional virus production. However, we find that further optimization would lead to a significant increase in the proofreading cost. Unexpected importance of the cost minimization is further supported by other global analyses. We speculate that cost optimization could help avoid cell defense responses. Thus, proofreading is essential for the production of functional viruses, but its rate is limited by energy costs.


Assuntos
Coronavirus/genética , Modelos Teóricos , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/metabolismo , Coronavirus/metabolismo , Cinética , Replicação Viral
10.
Arch Virol ; 166(7): 1811-1817, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33778918

RESUMO

Coronaviruses are a large family of important pathogens that cause human and animal diseases. At the end of 2019, a pneumonia epidemic caused by a novel coronavirus brought attention to coronaviruses. Exploring the interaction between the virus and its receptor will be helpful in developing preventive vaccines and therapeutic drugs. The coronavirus spike protein (S) plays an important role in both binding to receptors on host cells and fusion of the viral membrane with the host cell membrane. This review introduces the structure and function of the S protein and its receptor, focusing on the binding mode and binding region of both.


Assuntos
Coronavirus/metabolismo , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Sítios de Ligação , COVID-19/metabolismo , COVID-19/virologia , Coronavirus/química , Coronavirus/fisiologia , Humanos , Ligação Proteica , Conformação Proteica , Receptores Virais/classificação , SARS-CoV-2/química , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/classificação , Internalização do Vírus
11.
Viruses ; 13(2)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567791

RESUMO

Emerging viral diseases are a major threat to global health, and nearly two-thirds of emerging human infectious diseases are zoonotic. Most of the human epidemics and pandemics were caused by the spillover of viruses from wild mammals. Viruses that infect humans and a wide range of animals have historically caused devastating epidemics and pandemics. An in-depth understanding of the mechanisms of viral emergence and zoonotic spillover is still lacking. Receptors are major determinants of host susceptibility to viruses. Animal species sharing host cell receptors that support the binding of multiple viruses can play a key role in virus spillover and the emergence of novel viruses and their variants. Sialic acids (SAs), which are linked to glycoproteins and ganglioside serve as receptors for several human and animal viruses. In particular, influenza and coronaviruses, which represent two of the most important zoonotic threats, use SAs as cellular entry receptors. This is a comprehensive review of our current knowledge of SA receptor distribution among animal species and the range of viruses that use SAs as receptors. SA receptor tropism and the predicted natural susceptibility to viruses can inform targeted surveillance of domestic and wild animals to prevent the future emergence of zoonotic viruses.


Assuntos
Doenças Transmissíveis Emergentes/virologia , Coronavirus/metabolismo , Orthomyxoviridae/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Virais/metabolismo , Animais , Especificidade de Hospedeiro/fisiologia , Humanos , Ácidos Siálicos/metabolismo , Internalização do Vírus , Zoonoses/virologia
12.
PLoS Pathog ; 17(1): e1009033, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33411764

RESUMO

The p53 transcription factor plays a key role both in cancer and in the cell-intrinsic response to infections. The ORFEOME project hypothesized that novel p53-virus interactions reside in hitherto uncharacterized, unknown, or hypothetical open reading frames (orfs) of human viruses. Hence, 172 orfs of unknown function from the emerging viruses SARS-Coronavirus, MERS-Coronavirus, influenza, Ebola, Zika (ZIKV), Chikungunya and Kaposi Sarcoma-associated herpesvirus (KSHV) were de novo synthesized, validated and tested in a functional screen of p53 signaling. This screen revealed novel mechanisms of p53 virus interactions and two viral proteins KSHV orf10 and ZIKV NS2A binding to p53. Originally identified as the target of small DNA tumor viruses, these experiments reinforce the notion that all viruses, including RNA viruses, interfere with p53 functions. These results validate this resource for analogous systems biology approaches to identify functional properties of uncharacterized viral proteins, long non-coding RNAs and micro RNAs.


Assuntos
Doenças Transmissíveis Emergentes/virologia , Vírus de RNA/metabolismo , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/metabolismo , Vírus Chikungunya/genética , Vírus Chikungunya/metabolismo , Coronavirus/genética , Coronavirus/metabolismo , Ebolavirus/genética , Ebolavirus/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/metabolismo , Fases de Leitura Aberta , Vírus de RNA/genética , Proteína Supressora de Tumor p53/genética , Proteínas não Estruturais Virais/metabolismo , Zika virus/genética , Zika virus/metabolismo
13.
Infect Genet Evol ; 89: 104729, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33497837

RESUMO

In recent years, a total of seven human pathogenic coronaviruses (HCoVs) strains were identified, i.e., SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Here, we performed an analysis of the protease recognition sites and antigenic variation of the S-protein of these HCoVs. We showed tissue-specific expression pattern, functions, and a number of recognition sites of proteases in S-proteins from seven strains of HCoVs. In the case of SARS-CoV-2, we found two new protease recognition sites, each of calpain-2, pepsin-A, and caspase-8, and one new protease recognition site each of caspase-6, caspase-3, and furin. Our antigenic mapping study of the S-protein of these HCoVs showed that the SARS-CoV-2 virus strain has the most potent antigenic epitopes (highest antigenicity score with maximum numbers of epitope regions). Additionally, the other six strains of HCoVs show common antigenic epitopes (both B-cell and T-cell), with low antigenicity scores compared to SARS-CoV-2. We suggest that the molecular evolution of structural proteins of human CoV can be classified, such as (i) HCoV-NL63 and HCoV-229E, (ii) SARS-CoV-2, and SARS-CoV and (iii) HCoV-OC43 and HCoV-HKU1. In conclusion, we can presume that our study might help to prepare the interventions for the possible HCoVs outbreaks in the future.


Assuntos
Coronavirus/metabolismo , Peptídeo Hidrolases/metabolismo , Filogenia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Variação Antigênica , Sítios de Ligação , Coronavirus/classificação , Coronavirus/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Humanos , SARS-CoV-2/classificação , SARS-CoV-2/imunologia
14.
J Gen Virol ; 102(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33507143

RESUMO

Coronavirus protease nsp5 (Mpro, 3CLpro) remains a primary target for coronavirus therapeutics due to its indispensable and conserved role in the proteolytic processing of the viral replicase polyproteins. In this review, we discuss the diversity of known coronaviruses, the role of nsp5 in coronavirus biology, and the structure and function of this protease across the diversity of known coronaviruses, and evaluate past and present efforts to develop inhibitors to the nsp5 protease with a particular emphasis on new and mostly unexplored potential targets of inhibition. With the recent emergence of pandemic SARS-CoV-2, this review provides novel and potentially innovative strategies and directions to develop effective therapeutics against the coronavirus protease nsp5.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , SARS-CoV-2/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Inibidores de Protease Viral/uso terapêutico , Sequência de Aminoácidos , COVID-19/virologia , Coronavirus/enzimologia , Coronavirus/metabolismo , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Humanos , Filogenia , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismo
15.
Elife ; 102021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33463525

RESUMO

Seasonal coronaviruses (OC43, 229E, NL63, and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.


Assuntos
Adaptação Fisiológica/genética , Antígenos Virais/genética , Evolução Biológica , Coronavirus/metabolismo , Estações do Ano , Simulação por Computador , Coronavirus/genética , Regulação Viral da Expressão Gênica , Humanos , Vírus da Influenza A/genética , Vírus do Sarampo/genética , Filogenia
16.
Nucleic Acids Res ; 49(D1): D282-D287, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-32890396

RESUMO

SARS-CoV-2, the etiologic agent of COVID-19, exemplifies the general threat to global health posed by coronaviruses. The urgent need for effective vaccines and therapies is leading to a rapid rise in the number of high resolution structures of SARS-CoV-2 proteins that collectively reveal a map of virus vulnerabilities. To assist structure-based design of vaccines and therapeutics against SARS-CoV-2 and other coronaviruses, we have developed CoV3D, a database and resource for coronavirus protein structures, which is updated on a weekly basis. CoV3D provides users with comprehensive sets of structures of coronavirus proteins and their complexes with antibodies, receptors, and small molecules. Integrated molecular viewers allow users to visualize structures of the spike glycoprotein, which is the major target of neutralizing antibodies and vaccine design efforts, as well as sets of spike-antibody complexes, spike sequence variability, and known polymorphisms. In order to aid structure-based design and analysis of the spike glycoprotein, CoV3D permits visualization and download of spike structures with modeled N-glycosylation at known glycan sites, and contains structure-based classification of spike conformations, generated by unsupervised clustering. CoV3D can serve the research community as a centralized reference and resource for spike and other coronavirus protein structures, and is available at: https://cov3d.ibbr.umd.edu.


Assuntos
Biologia Computacional , Coronavirus/metabolismo , Bases de Dados de Proteínas , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/virologia , Epidemias , Humanos , Internet , Modelos Moleculares , Estrutura Terciária de Proteína , SARS-CoV-2/química , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
17.
Nucleic Acids Res ; 49(D1): D589-D599, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33245774

RESUMO

PAGER-CoV (http://discovery.informatics.uab.edu/PAGER-CoV/) is a new web-based database that can help biomedical researchers interpret coronavirus-related functional genomic study results in the context of curated knowledge of host viral infection, inflammatory response, organ damage, and tissue repair. The new database consists of 11 835 PAGs (Pathways, Annotated gene-lists, or Gene signatures) from 33 public data sources. Through the web user interface, users can search by a query gene or a query term and retrieve significantly matched PAGs with all the curated information. Users can navigate from a PAG of interest to other related PAGs through either shared PAG-to-PAG co-membership relationships or PAG-to-PAG regulatory relationships, totaling 19 996 993. Users can also retrieve enriched PAGs from an input list of COVID-19 functional study result genes, customize the search data sources, and export all results for subsequent offline data analysis. In a case study, we performed a gene set enrichment analysis (GSEA) of a COVID-19 RNA-seq data set from the Gene Expression Omnibus database. Compared with the results using the standard PAGER database, PAGER-CoV allows for more sensitive matching of known immune-related gene signatures. We expect PAGER-CoV to be invaluable for biomedical researchers to find molecular biology mechanisms and tailored therapeutics to treat COVID-19 patients.


Assuntos
Algoritmos , COVID-19/prevenção & controle , Biologia Computacional/métodos , Coronavirus/genética , Bases de Dados Genéticas , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/virologia , Coronavirus/metabolismo , Curadoria de Dados/métodos , Epidemias , Redes Reguladoras de Genes , Humanos , Armazenamento e Recuperação da Informação/métodos , Internet , Anotação de Sequência Molecular/métodos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Interface Usuário-Computador
18.
Microb Pathog ; 150: 104641, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33242646

RESUMO

Coronaviruses (CoVs) are causing a number of human and animal diseases because of their zoonotic nature such as Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19). These viruses can infect respiratory, gastrointestinal, hepatic and central nervous systems of human, livestock, birds, bat, mouse, and many wild animals. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerging respiratory virus and is causing CoVID-19 with high morbidity and considerable mortality. All CoVs belong to the order Nidovirales, family Coronaviridae, are enveloped positive-sense RNA viruses, characterised by club-like spikes on their surfaces and large RNA genome with a distinctive replication strategy. Coronavirus have the largest RNA genomes (~26-32 kilobases) and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. Non-structural proteins (nsp) 7-16 are cleaved from two large replicase polyproteins and guide the replication and processing of coronavirus RNA. Coronavirus replicase has more or less universal activities, such as RNA polymerase (nsp 12) and helicase (nsp 13), as well as a variety of unusual or even special mRNA capping (nsp 14, nsp 16) and fidelity regulation (nsp 14) domains. Besides that, several smaller subunits (nsp 7- nsp 10) serve as essential cofactors for these enzymes and contribute to the emerging "nsp interactome." In spite of the significant progress in studying coronaviruses structural and functional properties, there is an urgent need to understand the coronaviruses evolutionary success that will be helpful to develop enhanced control strategies. Therefore, it is crucial to understand the structure, function, and interactions of coronaviruses RNA synthesizing machinery and their replication strategies.


Assuntos
Coronavirus/fisiologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Animais , COVID-19/virologia , Coronavirus/química , Coronavirus/genética , Coronavirus/metabolismo , Genoma Viral , Humanos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Replicação Viral
19.
J Virol ; 95(3)2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33158944

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-related CoVs encode 3 tandem macrodomains within nonstructural protein 3 (nsp3). The first macrodomain, Mac1, is conserved throughout CoVs and binds to and hydrolyzes mono-ADP-ribose (MAR) from target proteins. Mac1 likely counters host-mediated antiviral ADP-ribosylation, a posttranslational modification that is part of the host response to viral infections. Mac1 is essential for pathogenesis in multiple animal models of CoV infection, implicating it as a virulence factor and potential therapeutic target. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose. SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 domains exhibit similar structural folds, and all 3 proteins bound to ADP-ribose with affinities in the low micromolar range. Importantly, using ADP-ribose-detecting binding reagents in both a gel-based assay and novel enzyme-linked immunosorbent assays (ELISAs), we demonstrated de-MARylating activity for all 3 CoV Mac1 proteins, with the SARS-CoV-2 Mac1 protein leading to a more rapid loss of substrate than the others. In addition, none of these enzymes could hydrolyze poly-ADP-ribose. We conclude that the SARS-CoV-2 and other CoV Mac1 proteins are MAR-hydrolases with similar functions, indicating that compounds targeting CoV Mac1 proteins may have broad anti-CoV activity.IMPORTANCE SARS-CoV-2 has recently emerged into the human population and has led to a worldwide pandemic of COVID-19 that has caused more than 1.2 million deaths worldwide. With no currently approved treatments, novel therapeutic strategies are desperately needed. All coronaviruses encode a highly conserved macrodomain (Mac1) that binds to and removes ADP-ribose adducts from proteins in a dynamic posttranslational process that is increasingly being recognized as an important factor that regulates viral infection. The macrodomain is essential for CoV pathogenesis and may be a novel therapeutic target. Thus, understanding its biochemistry and enzyme activity are critical first steps for these efforts. Here, we report the crystal structure of SARS-CoV-2 Mac1 in complex with ADP-ribose and describe its ADP-ribose binding and hydrolysis activities in direct comparison to those of SARS-CoV and MERS-CoV Mac1 proteins. These results are an important first step for the design and testing of potential therapies targeting this unique protein domain.


Assuntos
N-Glicosil Hidrolases/metabolismo , SARS-CoV-2/enzimologia , Proteínas não Estruturais Virais/metabolismo , Adenosina Difosfato Ribose/química , Adenosina Difosfato Ribose/metabolismo , Sequência de Aminoácidos , Coronavirus/química , Coronavirus/enzimologia , Coronavirus/metabolismo , Cristalografia por Raios X , Humanos , Hidrólise , Cinética , N-Glicosil Hidrolases/química , Ligação Proteica , Domínios Proteicos , SARS-CoV-2/química , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/química
20.
Pharmacol Res Perspect ; 9(1): e00691, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33378565

RESUMO

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Infecções por Coronavirus/metabolismo , Coronavirus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Azóis/administração & dosagem , Azóis/metabolismo , COVID-19/tratamento farmacológico , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Naftoquinonas/administração & dosagem , Naftoquinonas/metabolismo , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/metabolismo , Síndrome Respiratória Aguda Grave/tratamento farmacológico
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