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1.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-33184246

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment of constipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein-ACE2 interface by making substantial π-π interactions with Tyr505 in the 'Site 1' hook region of RBD and hydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the protein throughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may be a promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entry into the host.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Oxazinas/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Antivirais/química , Antivirais/uso terapêutico , Infecções por Coronavirus/virologia , Humanos , Laxantes/química , Laxantes/uso terapêutico , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia , Conformação Proteica
2.
Molecules ; 25(21)2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33147850

RESUMO

Zebrafish has been a reliable model system for studying human viral pathologies. SARS-CoV-2 viral infection has become a global chaos, affecting millions of people. There is an urgent need to contain the pandemic and develop reliable therapies. We report the use of a humanized zebrafish model, xeno-transplanted with human lung epithelial cells, A549, for studying the protective effects of a tri-herbal medicine Coronil. At human relevant doses of 12 and 58 µg/kg, Coronil inhibited SARS-CoV-2 spike protein, induced humanized zebrafish mortality, and rescued from behavioral fever. Morphological and cellular abnormalities along with granulocyte and macrophage accumulation in the swim bladder were restored to normal. Skin hemorrhage, renal cell degeneration, and necrosis were also significantly attenuated by Coronil treatment. Ultra-high-performance liquid chromatography (UHPLC) analysis identified ursolic acid, betulinic acid, withanone, withaferine A, withanoside IV-V, cordifolioside A, magnoflorine, rosmarinic acid, and palmatine as phyto-metabolites present in Coronil. In A549 cells, Coronil attenuated the IL-1ß induced IL-6 and TNF-α cytokine secretions, and decreased TNF-α induced NF-κB/AP-1 transcriptional activity. Taken together, we show the disease modifying immunomodulatory properties of Coronil, at human equivalent doses, in rescuing the pathological features induced by the SARS-CoV-2 spike protein, suggesting its potential use in SARS-CoV-2 infectivity.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Sacos Aéreos/efeitos dos fármacos , Sacos Aéreos/virologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Febre/tratamento farmacológico , Febre/etiologia , Hemorragia/prevenção & controle , Humanos , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Necrose/patologia , Necrose/prevenção & controle , Pandemias , Fitoterapia , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Mucosa Respiratória/transplante , Ativação Transcricional/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Peixe-Zebra
3.
Front Immunol ; 11: 552925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072093

RESUMO

Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus , Sistemas de Liberação de Medicamentos , Pandemias , Pneumonia Viral , Internalização do Vírus/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Humanos , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Serina Endopeptidases/imunologia , Inibidores de Serino Proteinase/uso terapêutico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/imunologia , Células Th2/imunologia , Vacinas Virais/imunologia , Vacinas Virais/uso terapêutico
4.
PLoS One ; 15(10): e0240004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33002032

RESUMO

The SARS-CoV-2 virus has caused a pandemic and is public health emergency of international concern. As of now, no registered therapies are available for treatment of coronavirus infection. The viral infection depends on the attachment of spike (S) glycoprotein to human cell receptor angiotensin-converting enzyme 2 (ACE2). We have designed a protein inhibitor (ΔABP-D25Y) targeting S protein using computational approach. The inhibitor consists of two α helical peptides homologues to protease domain (PD) of ACE2. Docking studies and molecular dynamic simulation revealed that the inhibitor binds exclusively at the ACE2 binding site of S protein. The computed binding affinity of the inhibitor is higher than the ACE2 and thus will likely out compete ACE2 for binding to S protein. Hence, the proposed inhibitor ΔABP-D25Y could be a potential blocker of S protein and receptor binding domain (RBD) attachment.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Desenho de Fármacos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Homologia Estrutural de Proteína , Sítios de Ligação , Simulação por Computador , Infecções por Coronavirus , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral , Domínios Proteicos
5.
Signal Transduct Target Ther ; 5(1): 220, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024075
6.
Science ; 370(6515): 426-431, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32907861

RESUMO

Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 0.16 nanograms per milliliter). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Desenho de Fármacos , Peptidil Dipeptidase A/química , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação , Chlorocebus aethiops , Infecções por Coronavirus , Microscopia Crioeletrônica , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral , Ligação Proteica/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/química , Células Vero
7.
Bratisl Lek Listy ; 121(10): 705-711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955901

RESUMO

BACKGROUND: COVID-19 is not fully known and causes severe inflammation and cytokine storm. It has many symptoms, such as: fever, sore throat, headache, dyspnoea, and diarrhoea. Arbidol was used in the treatment of COVID19, which was the most critical health problem in the world. However, the desired recovery was not achieved with Arbidol. Many countries still use this drug in the treatment of COVID19. AIM: We aimed to determine whether Arbidol, the hemagglutinin esterase inhibitor used in the treatment of COVID-19, was effective against SARS Cov-2 in silico. RESULTS AND CONCLUSION: The similarity between hemagglutinin and spike proteins were reported due to the fact that inhibition properties of Arbidol and its 39 analogues were examined in detail against hemagglutinin esterase and spike glycoproteins. CID 1070884 and CID 1207786 were found to be more active against hemagglutinin esterase than in Arbidol, while these compounds were inactive against spike glycoproteins. The interaction mechanism was clarified between arbidol and spike proteins. Phenylalanine, tyrosine, glycine, lysine, and aspartic acid were found to be the headliner amino acids in the interactions between Arbidol and binding domains of spike glycoproteins in the SARS-CoV2 (Tab. 3, Fig. 8, Ref. 28).


Assuntos
Betacoronavirus/efeitos dos fármacos , Indóis/farmacologia , Sítios de Ligação , Infecções por Coronavirus , Humanos , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores
8.
Curr Top Med Chem ; 20(26): 2362-2378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32962613

RESUMO

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Glicoproteína da Espícula de Coronavírus/genética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Betacoronavirus/ultraestrutura , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva/métodos , Ivermectina/uso terapêutico , Modelos Moleculares , Niclosamida/uso terapêutico , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Estrutura Secundária de Proteína , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Vírus da SARS/ultraestrutura , Síndrome Respiratória Aguda Grave , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/biossíntese
9.
PLoS Pathog ; 16(9): e1008796, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913364

RESUMO

There is an urgent need for effective treatment and preventive vaccine to contain this devastating global pandemic, which requires a comprehensive understanding of humoral responses specific to SARS-CoV-2 during the disease progression and convalescent phase of COVID-19 patients. We continuously monitored the serum IgM and IgG responses specific to four SARS-CoV-2 related antigens, including the nucleoprotein (NP), receptor binding domain (RBD), S1 protein, and ectodomain (ECD) of the spike protein among non-severe and severe COVID-19 patients for seven weeks since disease onset. Most patients generated humoral responses against NP and spike protein-related antigens but with their distinct kinetics profiles. Combined detection of NP and ECD antigens as detecting antigen synergistically improved the sensitivity of the serological assay, compared to that of using NP or RBD as detection antigen. 80.7% of convalescent sera from COVID-19 patients revealed that the varying extents of neutralization activities against SARS-CoV-2. S1-specific and ECD-specific IgA responses were strongly correlated with the neutralization activities in non-severe patients, but not in severe patients. Moreover, the neutralizing activities of the convalescent sera were shown to significantly decline during the period between 21 days to 28 days after hospital discharge, accompanied by a substantial drop in RBD-specific IgA response. Our data provide evidence that are crucial for serological testing, antibody-based intervention, and vaccine design of COVID-19.


Assuntos
Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/patogenicidade , Humanos , Imunoglobulina G/sangue , Estudos Longitudinais , Pandemias , Testes Sorológicos , Glicoproteína da Espícula de Coronavírus/imunologia
10.
Nat Commun ; 11(1): 4420, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887876

RESUMO

SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this interaction presents an attractive possibility for suppressing SARS-CoV-2 replication. Here, we report the isolation and characterization of an alpaca-derived single domain antibody fragment, Ty1, that specifically targets the receptor binding domain (RBD) of the SARS-CoV-2 spike, directly preventing ACE2 engagement. Ty1 binds the RBD with high affinity, occluding ACE2. A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that Ty1 binds to an epitope on the RBD accessible in both the 'up' and 'down' conformations, sterically hindering RBD-ACE2 binding. While fusion to an Fc domain renders Ty1 extremely potent, Ty1 neutralizes SARS-CoV-2 spike pseudovirus as a 12.8 kDa nanobody, which can be expressed in high quantities in bacteria, presenting opportunities for manufacturing at scale. Ty1 is therefore an excellent candidate as an intervention against COVID-19.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/efeitos dos fármacos , Camelídeos Americanos/imunologia , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Anticorpos de Domínio Único/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Sítios de Ligação , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Microscopia Crioeletrônica , Epitopos/imunologia , Epitopos/metabolismo , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Pandemias , Peptidil Dipeptidase A/química , Pneumonia Viral/virologia , Ligação Proteica , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
11.
Trials ; 21(1): 691, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736596

RESUMO

OBJECTIVES: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95 , registered 28th April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Antivirais/efeitos adversos , Benzamidas/uso terapêutico , Hospitalização , Humanos , Pandemias , Pirazinas/uso terapêutico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Padrão de Cuidado
12.
F1000Res ; 9: 663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765844

RESUMO

Background: Human coronavirus (SARS-CoV-2) is causing a pandemic with significant morbidity and mortality. As no effective novel drugs are available currently, drug repurposing is an alternative intervention strategy. Here we present an  in silico drug repurposing study that implements successful concepts of computer-aided drug design (CADD) technology for repurposing known drugs to interfere with viral cellular entry via the spike glycoprotein (SARS-CoV-2-S), which mediates host cell entry via the hACE2 receptor. Methods: A total of 4015 known and approved small molecules were screened for interaction with SARS-CoV-2-S through docking studies and 15 lead molecules were shortlisted. Additionally, streptomycin, ciprofloxacin, and glycyrrhizic acid (GA) were selected based on their reported anti-viral activity, safety, availability and affordability. The 18 molecules were subjected to molecular dynamics (MD) simulation. Results: The MD simulation results indicate that GA of plant origin may be repurposed for SARS-CoV-2 intervention, pending further studies. Conclusions: Repurposing is a beneficial strategy for treating COVID-19 with existing drugs. It is aimed at using docking studies to screen molecules for clinical application and investigating their efficacy in inhibiting SARS-CoV-2-S. SARS-CoV-2-S is a key pathogenic protein that mediates pathogen-host interaction. Hence, the molecules screened for inhibitory properties against SARS-CoV-2-S can be clinically used to treat COVID-19 since the safety profile is already known.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Desenho de Fármacos , Reposicionamento de Medicamentos , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A , Internalização do Vírus/efeitos dos fármacos
13.
Cell Physiol Biochem ; 54(4): 767-790, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32830930

RESUMO

The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/fisiologia , Coronaviridae/patogenicidade , Infecções por Coronaviridae/epidemiologia , Infecções por Coronaviridae/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Previsões , Genoma Viral , Saúde Global , Humanos , Imunidade Coletiva , Imunização Passiva , Pandemias/prevenção & controle , Peptídeo Hidrolases/farmacologia , Peptídeo Hidrolases/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , RNA Viral/genética , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas Virais , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Zoonoses
14.
Adv Biol Regul ; 77: 100739, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773105

RESUMO

The COVID-19 pandemic has put a serious strain on health treatments as well at the economies of many nations. Unfortunately, there is not currently available vaccine for SARS-Cov-2/COVID-19. Various types of patients have delayed treatment or even routine check-ups and we are adapting to a virtual world. In many cases, surgeries are delayed unless they are essential. This is also true with regards to cancer treatments and screening. Interestingly, some existing drugs and nutraceuticals have been screened for their effects on COVID-19. Certain FDA approved drugs, vitamin, natural products and trace minerals may be repurposed to treat or improve the prevention of COVID-19 infections and disease progression. This review article will summarize how the treatments of various cancer patients has changed during the COVID-19 era as well as discuss the promise of some existing drugs and other agents to be repurposed to treat this disease.


Assuntos
Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Comorbidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/uso terapêutico , Neoplasias/imunologia , Neoplasias/virologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Oligoelementos/uso terapêutico , Vitaminas/uso terapêutico
15.
Front Immunol ; 11: 1664, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754161

RESUMO

The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.


Assuntos
Betacoronavirus/fisiologia , Simulação por Computador , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Interface Usuário-Computador , Internalização do Vírus/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/virologia , Genoma Viral/genética , Humanos , Modelos Genéticos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Ligação Viral
16.
F1000Res ; 9: 576, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802318

RESUMO

Background: There are no known medicines or vaccines to control the COVID-19 pandemic caused by SARS-CoV-2 (nCoV). Antiviral peptides are superior to conventional drugs and may also be effective against COVID-19. Hence, we investigated the SARS-CoV-2 Spike receptor-binding domain (nCoV-RBD) that interacts with hACE2 for viral attachment and entry. Methods: Three strategies and bioinformatics approaches were employed to design potential nCoV-RBD - hACE2 interaction-blocking peptides that may restrict viral attachment and entry. Firstly, the key residues interacting with nCoV-RBD - hACE2 are identified and hACE2 sequence-based peptides are designed. Second, peptides from five antibacterial peptide databases that block nCoV-RBD are identified; finally, a chimeric peptide design approach is used to design peptides that can bind to key nCoV-RBD residues. The final peptides are selected based on their physiochemical properties, numbers and positions of key residues binding, binding energy, and antiviral properties. Results: We found that: (i) three amino acid stretches in hACE2 interact with nCoV-RBD; (ii) effective peptides must bind to three key positions of nCoV-RBD (Gly485/Phe486/Asn487, Gln493, and Gln498/Thr500/Asn501); (iii) Phe486, Gln493, and Asn501 are critical residues; (iv) AC20 and AC23 derived from hACE2 may block two key critical positions; (iv) DBP6 identified from databases can block the three sites of the nCoV-RBD and interacts with one critical position, Gln498; (v) seven chimeric peptides were considered promising, among which cnCoVP-3, cnCoVP-4, and cnCoVP-7 are the top three; and (vi) cnCoVP-4 meets all the criteria and is the best peptide. Conclusions: To conclude, using three different bioinformatics approaches, we identified 17 peptides that can potentially bind to the nCoV-RBD that interacts with hACE2. Binding these peptides to nCoV-RBD may potentially inhibit the virus to access hACE2 and thereby may prevent the infection. Out of 17, 10 peptides have promising potential and need further experimental validation.


Assuntos
Infecções por Coronavirus , Pandemias , Peptídeos/farmacologia , Peptidil Dipeptidase A/química , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Betacoronavirus , Humanos , Receptores Virais/química
17.
Sci Rep ; 10(1): 13866, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807895

RESUMO

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


Assuntos
Betacoronavirus/efeitos dos fármacos , Biologia Computacional/métodos , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Betacoronavirus/química , Sítios de Ligação , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Simeprevir/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo
18.
Int J Antimicrob Agents ; 56(3): 106119, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32738306

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported improved outcomes resulting from an effective reduction or absence of viral load when patients were treated with chloroquine (CQ) or hydroxychloroquine (HCQ). In addition, the effects of these drugs were improved by simultaneous administration of azithromycin (AZM). The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptor, allowing virus entry and replication in host cells. The viral main protease (Mpro) and host cathepsin L (CTSL) are among the proteolytic systems involved in SARS-CoV-2 S protein activation. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. The findings showed AZM affinity scores (ΔG) with strong interactions with ACE2, CTSL, Mpro and RBD. CQ affinity scores showed three low-energy results (less negative) with ACE2, CTSL and RBD, and a firm bond score with Mpro. For HCQ, two results (ACE2 and Mpro) were firmly bound to the receptors, however CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between HCQ and CQ with ACE2 and Mpro were probably due to structural differences between the drugs. On other hand, AZM not only showed more negative (better) values in affinity, but also in the number of interactions in all targets. Nevertheless, further studies are needed to investigate the antiviral properties of these drugs against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Azitromicina/química , Betacoronavirus/química , Catepsina L/química , Cloroquina/química , Cisteína Endopeptidases/química , Hidroxicloroquina/química , Peptidil Dipeptidase A/química , Glicoproteína da Espícula de Coronavírus/química , Proteínas não Estruturais Virais/química , Motivos de Aminoácidos , Antivirais/química , Azitromicina/farmacologia , Betacoronavirus/metabolismo , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/metabolismo , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Hidroxicloroquina/farmacologia , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Ligação Viral/efeitos dos fármacos
19.
J Biosci ; 452020.
Artigo em Inglês | MEDLINE | ID: mdl-32661214

RESUMO

The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARSCoV- 2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.


Assuntos
Corticosteroides/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Fatores Imunológicos/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Progressão da Doença , Descoberta de Drogas , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/uso terapêutico , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
20.
Curr Top Med Chem ; 20(24): 2210-2220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32648845

RESUMO

World Health Organization declared coronavirus disease (COVID-19) caused by SARS coronavirus-2 (SARS-CoV-2) as pandemic. Its outbreak started in China in Dec 2019 and rapidly spread all over the world. SARS-CoV-2 has infected more than 800,000 people and caused about 35,000 deaths so far, moreover, no approved drugs are available to treat COVID-19. Several investigations have been carried out to identify potent drugs for COVID-19 based on drug repurposing, potential novel compounds from ligand libraries, natural products, short peptides, and RNAseq analysis. This review is focused on three different aspects; (i) targets for drug design (ii) computational methods to identify lead compounds and (iii) drugs for COVID-19. It also covers the latest literature on various hit molecules proposed by computational methods and experimental techniques.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Biologia Computacional , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Pandemias , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores
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