scholarly journals Cloroquina: mecanismos de ação, efeitos colaterais e revisão de estudos sobre seu uso contra o SARS-CoV-2

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Diogo Martins Ribeiro ◽  
André Tomaz Terra Júnior ◽  
Edson Rodrigues Cavalcante
Keyword(s):  
England Journal ◽  
Severe Acute Respiratory Syndrome ◽  
New England ◽  
Academic Journals

A Cloroquina é uma 4-aminoquinolina da classe dos agregados anfifílicos catiônicos que tem chamado a atenção da comunidade científica devido aos seus efeitos antivirais. Inicialmente utilizada contra a malária, essa droga e principalmente sua derivada, Hidroxicloroquina, passaram a ser aplicadas na prática reumatológica e contra o Lúpus Eritematoso Sistêmico. Apesar de seu efeito contra diferentes doenças virais, ainda não é sabido se a Cloroquina é efetiva contra o COVID-19, doença causada pelo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Objetivando entender sobre o potencial da Cloroquina contra o novo coronavírus, uma busca de estudos originais foi feita na base de dados PubMed e especificamente em Oxford Academic Journals, The New England Journal of Medicine, Springer Nature, Nature Research e JAMA. Estudos in vitro parecem ser concordantes quanto aos benefícios da Cloroquina e sua derivada, Hidroxicloroquina, contra o SARS-CoV-2. Estudos in vivo, no entanto, demonstram resultados controversos de ambas as drogas em relação ao tratamento ou profilaxia do COVID-19, sugerindo a necessidade de mais estudos.  

scholarly journals Revisão Sobre O Uso Da Cloroquina E Da Hidroxicloroquina No Tratamento Dos Pacientes Acometidos Pela Covid-19

2021 ◽  
pp. 43-64
Author(s):  
Jhosyton Correia Chaves ◽  
Thiely Rodrigues Ott
Keyword(s):  
England Journal ◽  
New England

O novo Coronavírus (SARS-Cov 2) foi identificado em Wuhan, China. Rapidamente se espalhou pelo mundo causando a Covid-19 e se tornou uma Pandemia, declarada em março, pela OMS. Visando obter um tratamento eficaz contra a doença, diversas pesquisas desenvolveram testes com dois medicamentos: Cloroquina e Hidroxicloroquina, associadas ou não a outros medicamentos. A Cloroquina e a Hidroxicloroquina são medicamentos antigos, utilizados principalmente para tratamento da Malária, além de serem medicamentos considerados essenciais em sistemas de Saúde pela OMS. Apesar de sua segurança e eficácia, existem efeitos tóxicos no uso dos medicamentos, especialmente da Cloroquina. Entre os efeitos relatados, estão a toxicidade ocular, enjoos, náuseas e problemas intestinais. Os dados presentes neste trabalho foram obtidos através de pesquisas na literatura utilizando palavras-chave específicas para encontrar resultados requeridos em portais como Scielo, Scholar Google, The New England Journal Of Medicine e The Lancet. O objetivo deste trabalho foi verificar a eficácia da Cloroquina e da Hidroxicloroquina, associadas ou não a outros medicamentos nos testes clínicos encontrados na literatura. Os resultados demonstram que os medicamentos, apesar de demonstrarem algum potencial in vitro, não indicam resultados benéficos in vivo, na maioria dos trabalhos consultados, não diminuindo o risco de morte, desenvolvimento ou sintomas da Covid-19. Um único artigo foi totalmente favorável ao uso, mas os dados e os métodos utilizados pelo mesmo contêm muitas limitações como a desistência de pacientes e a morte de outros ao longo dos dias de tratamento.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

scholarly journals Identification of Common Deletions in the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Zhe Liu ◽  
Huanying Zheng ◽  
Huifang Lin ◽  
Mingyue Li ◽  
Runyu Yuan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Virus Replication ◽  
Receptor Binding ◽  
Cleavage Site ◽  
Spike Protein ◽  
Clinical Samples ◽  
Receptor Binding Domain ◽  
Flanking Sequence

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus first identified in December 2019. Notable features that make SARS-CoV-2 distinct from most other previously identified betacoronaviruses include a receptor binding domain and a unique insertion of 12 nucleotides or 4 amino acids (PRRA) at the S1/S2 boundary. In this study, we identified two deletion variants of SARS-CoV-2 that either directly affect the polybasic cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN). These deletions were verified by multiple sequencing methods. In vitro results showed that the deletion of NSPRRAR likely does not affect virus replication in Vero and Vero-E6 cells; however, the deletion of QTQTN may restrict late-phase viral replication. The deletion of QTQTN was detected in 3 of 68 clinical samples and 12 of 24 in vitro-isolated viruses, while the deletion of NSPRRAR was identified in 3 in vitro-isolated viruses. Our data indicate that (i) there may be distinct selection pressures on SARS-CoV-2 replication or infection in vitro and in vivo; (ii) an efficient mechanism for deleting this region from the viral genome may exist, given that the deletion variant is commonly detected after two rounds of cell passage; and (iii) the PRRA insertion, which is unique to SARS-CoV-2, is not fixed during virus replication in vitro. These findings provide information to aid further investigation of SARS-CoV-2 infection mechanisms and a better understanding of the NSPRRAR deletion variant observed here. IMPORTANCE The spike protein determines the infectivity and host range of coronaviruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has two unique features in its spike protein, the receptor binding domain and an insertion of 12 nucleotides at the S1/S2 boundary resulting in a furin-like cleavage site. Here, we identified two deletion variants of SARS-CoV-2 that either directly affect the furin-like cleavage site itself (NSPRRAR) or a flanking sequence (QTQTN), and we investigated these deletions in cell isolates and clinical samples. The absence of the polybasic cleavage site in SARS-CoV-2 did not affect virus replication in Vero or Vero-E6 cells. Our data indicate the PRRAR sequence and the flanking QTQTN sequence are not fixed in vitro; thus, there appears to be distinct selection pressures on SARS-CoV-2 sequences in vitro and in vivo. Further investigation of the mechanism of generating these deletion variants and their infectivity in different animal models would improve our understanding of the origin and evolution of this virus.

scholarly journals Escape from Human Monoclonal Antibody Neutralization Affects In Vitro and In Vivo Fitness of Severe Acute Respiratory Syndrome Coronavirus

2010 ◽  
Vol 201 (6) ◽  
pp. 946-955 ◽  
Author(s):  
Barry Rockx ◽  
Eric Donaldson ◽  
Matthew Frieman ◽  
Timothy Sheahan ◽  
Davide Corti ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Severe Acute Respiratory Syndrome ◽  
Human Monoclonal Antibody ◽  
Antibody Neutralization

scholarly journals The Open Reading Frame 3a Protein of Severe Acute Respiratory Syndrome-Associated Coronavirus Promotes Membrane Rearrangement and Cell Death

2009 ◽  
Vol 84 (2) ◽  
pp. 1097-1109 ◽  
Author(s):  
Eric C. Freundt ◽  
Li Yu ◽  
Cynthia S. Goldsmith ◽  
Sarah Welsh ◽  
Aaron Cheng ◽  
...  
Keyword(s):  
Cell Death ◽  
Severe Acute Respiratory Syndrome ◽  
Vero Cells ◽  
Small Gtpase ◽  
Open Reading Frames ◽  
Accessory Proteins ◽  
Reading Frame ◽  
Golgi Fragmentation

ABSTRACT The genome of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) contains eight open reading frames (ORFs) that encode novel proteins. These accessory proteins are dispensable for in vitro and in vivo replication and thus may be important for other aspects of virus-host interactions. We investigated the functions of the largest of the accessory proteins, the ORF 3a protein, using a 3a-deficient strain of SARS-CoV. Cell death of Vero cells after infection with SARS-CoV was reduced upon deletion of ORF 3a. Electron microscopy of infected cells revealed a role for ORF 3a in SARS-CoV induced vesicle formation, a prominent feature of cells from SARS patients. In addition, we report that ORF 3a is both necessary and sufficient for SARS-CoV-induced Golgi fragmentation and that the 3a protein accumulates and localizes to vesicles containing markers for late endosomes. Finally, overexpression of ADP-ribosylation factor 1 (Arf1), a small GTPase essential for the maintenance of the Golgi apparatus, restored Golgi morphology during infection. These results establish an important role for ORF 3a in SARS-CoV-induced cell death, Golgi fragmentation, and the accumulation of intracellular vesicles.

scholarly journals Does SARS-CoV-2 Trigger Stress-Induced Autoimmunity by Molecular Mimicry? A Hypothesis

2020 ◽  
Vol 9 (7) ◽  
pp. 2038 ◽  
Author(s):  
Francesco Cappello ◽  
Antonella Marino Gammazza ◽  
Francesco Dieli ◽  
Everly Conway de Macario ◽  
Alberto JL Macario
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Molecular Mimicry ◽  
Short Review ◽  
Working Hypothesis ◽  
In Vivo Tests ◽  
Autoimmune Phenomena ◽  
Effective Treatments

Viruses can generate molecular mimicry phenomena within their hosts. Why should severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not be considered one of these? Information in this short review suggests that it might be so and, thus, encourages research aiming at testing this possibility. We propose, as a working hypothesis, that the virus induces antibodies and that some of them crossreact with host’s antigens, thus eliciting autoimmune phenomena with devasting consequences in various tissues and organs. If confirmed, by in vitro and in vivo tests, this could drive researchers to find effective treatments against the virus.

scholarly journals Severe Acute Respiratory Syndrome Coronavirus Protein 6 Accelerates Murine Coronavirus Infections

2006 ◽  
Vol 81 (3) ◽  
pp. 1220-1229 ◽  
Author(s):  
Chandra Tangudu ◽  
Heidi Olivares ◽  
Jason Netland ◽  
Stanley Perlman ◽  
Thomas Gallagher
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Open Reading Frames ◽  
Viral Rna ◽  
Protein Accumulation ◽  
Sars Coronavirus ◽  
Viral Rnas ◽  
Growth Properties ◽  
Murine Coronavirus

ABSTRACT One or more of the unique 3′-proximal open reading frames (ORFs) of the severe acute respiratory syndrome (SARS) coronavirus may encode determinants of virus virulence. A prime candidate is ORF6, which encodes a 63-amino-acid membrane-associated peptide that can dramatically increase the lethality of an otherwise attenuated JHM strain of murine coronavirus (L. Pewe, H. Zhou, J. Netland, C. Tangudu, H. Olivares, L. Shi, D. Look, T. Gallagher, and S. Perlman, J. Virol. 79:11335-11342, 2005). To discern virulence mechanisms, we compared the in vitro growth properties of rJ.6, a recombinant JHM expressing the SARS peptide, with isogenic rJ.6-KO, which has an inactive ORF containing a mutated initiation codon and a termination codon at internal position 27. The rJ.6 infections proceeded rapidly, secreting progeny about 1.5 h earlier than rJ.6-KO infections did. The rJ.6 infections were also set apart by early viral protein accumulation and by robust expansion via syncytia, a characteristic feature of JHM virus dissemination. We found no evidence for protein 6 operating at the virus entry or assembly stage, as virions from either infection were indistinguishable. Rather, protein 6 appeared to operate by fostering viral RNA and protein synthesis, as RNA quantifications by reverse transcription-quantitative PCR revealed viral RNA levels in the rJ.6 cultures that were five to eight times higher than those lacking protein 6. Furthermore, protein 6 coimmunoprecipitated with viral RNAs and colocalized on cytoplasmic vesicles with replicating viral RNAs. The SARS coronavirus encodes a novel membrane protein 6 that can accelerate replication of a related mouse virus, a property that may explain its ability to increase in vivo virus virulence.

scholarly journals Broad human and animal coronavirus neutralisation by SARS-CoV-2 S2-targeted vaccination

2021 ◽  
Author(s):  
Kevin W. Ng ◽  
Nikhil Faulkner ◽  
Katja Finsterbusch ◽  
Mary Wu ◽  
Ruth Harvey ◽  
...  
Keyword(s):  
Immune System ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Antibody Response ◽  
Common Cold ◽  
Cross Reactivity ◽  
Antibody Responses ◽  
History Of

AbstractSeveral common-cold coronaviruses (HCoVs) are endemic in humans and several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current Coronavirus disease 2019 (COVID-19) pandemic. Whilst antibody cross-reactivity with the Spike glycoproteins (S) of diverse coronaviruses has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to or mediate protection, when induced naturally or through vaccination. Using a mouse model, we show that prior HCoV-OC43 S immunity primes neutralising antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, mouse vaccination with SARS-CoV-2 S2 elicits antibodies that neutralise diverse animal and human alphacoronaviruses and betacoronaviruses in vitro, and protects against SARS-CoV-2 challenge in vivo. Lastly, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induces stronger and broader neutralising antibody response than booster Wuhan S vaccination, suggesting it may prevent repertoire focusing caused by repeated homologous vaccination. The data presented here establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern (VOCs), as well as to unpredictable, yet inevitable future coronavirus zoonoses.

scholarly journals The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2

2021 ◽  
Author(s):  
Andrea L. Cathcart ◽  
Colin Havenar-Daughton ◽  
Florian A. Lempp ◽  
Daphne Ma ◽  
Michael Schmid ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Host Cells ◽  
Infection Model ◽  
Dual Function ◽  
Resistance Mutations ◽  
Viral Respiratory Infection ◽  
Dual Action

ABSTRACTVIR-7831 and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VIR-7831 and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an “LS” mutation in the Fc region to prolong serum half-life and potentially enhance distribution to the respiratory mucosa. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. VIR-7831 and VIR-7832 potently neutralize live wild-type SARS-CoV-2 in vitro as well as pseudotyped viruses encoding spike protein from the B.1.1.7, B.1.351 and P.1 variants. In addition, they retain activity against monoclonal antibody resistance mutations that confer reduced susceptibility to currently authorized mAbs. The VIR-7831/VIR-7832 epitope does not overlap with mutational sites in the current variants of concern and continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept wildtype SARS-CoV-2 infection model, animals treated with VIR-7831 had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that VIR-7831 and VIR-7832 are promising new agents in the fight against COVID-19.

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