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1.
Nat Commun ; 11(1): 4935, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004797

RESUMO

Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Gramicidina/análogos & derivados , Ensaios de Triagem em Larga Escala/métodos , Animais , Antibacterianos/química , Linhagem Celular Tumoral , Química Farmacêutica , Eritrócitos , Estudos de Viabilidade , Bactérias Gram-Positivas/efeitos dos fármacos , Gramicidina/química , Gramicidina/farmacologia , Hemólise/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Coelhos , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
2.
Int J Immunopathol Pharmacol ; 34: 2058738420966078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33045858

RESUMO

Given the sharp spreading of COVID-19 pandemic all around the world, our attention was brought to consider that that many cationic drugs (i.e. those characterized by the presence, at physiological pH value, of one or more cationic groups, both primary, secondary, tertiary and guanidinic aminic groups) could have any effect in impairing SARS-CoV2 entry in the host cell. This could open to new therapeutic chances against COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , Pandemias , Pneumonia Viral/epidemiologia
3.
Sci Rep ; 10(1): 14290, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868801

RESUMO

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Descoberta de Drogas , Pneumonia Viral/virologia , Amidas/química , Amidas/farmacologia , Antivirais/química , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/diagnóstico , Descoberta de Drogas/métodos , Humanos , Lopinavir/química , Lopinavir/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pandemias , Pneumonia Viral/diagnóstico , Pirazinas/química , Pirazinas/farmacologia , Ritonavir/química , Ritonavir/farmacologia
4.
PLoS One ; 15(9): e0238907, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915876

RESUMO

BACKGROUND: COVID-19 is a critical pandemic that has affected human communities worldwide, and there is an urgent need to develop effective drugs. Although there are a large number of candidate drug compounds that may be useful for treating COVID-19, the evaluation of these drugs is time-consuming and costly. Thus, screening to identify potentially effective drugs prior to experimental validation is necessary. METHOD: In this study, we applied the recently proposed method tensor decomposition (TD)-based unsupervised feature extraction (FE) to gene expression profiles of multiple lung cancer cell lines infected with severe acute respiratory syndrome coronavirus 2. We identified drug candidate compounds that significantly altered the expression of the 163 genes selected by TD-based unsupervised FE. RESULTS: Numerous drugs were successfully screened, including many known antiviral drug compounds such as C646, chelerythrine chloride, canertinib, BX-795, sorafenib, sorafenib, QL-X-138, radicicol, A-443654, CGP-60474, alvocidib, mitoxantrone, QL-XII-47, geldanamycin, fluticasone, atorvastatin, quercetin, motexafin gadolinium, trovafloxacin, doxycycline, meloxicam, gentamicin, and dibromochloromethane. The screen also identified ivermectin, which was first identified as an anti-parasite drug and recently the drug was included in clinical trials for SARS-CoV-2. CONCLUSIONS: The drugs screened using our strategy may be effective candidates for treating patients with COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Descoberta de Drogas/métodos , Aprendizado de Máquina não Supervisionado , Células A549 , Antivirais/química , Antivirais/classificação , Humanos
5.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913008

RESUMO

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.


Assuntos
Antivirais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Vimentina/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Regulação para Baixo , Descoberta de Drogas/métodos , Humanos , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptores Virais , Replicação Viral/fisiologia
6.
Nat Commun ; 11(1): 4903, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994412

RESUMO

The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.


Assuntos
Sistemas CRISPR-Cas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas/métodos , Edição de Genes/métodos , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína 9 Associada à CRISPR/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Doxiciclina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/genética , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Transgênicos , RNA Guia/genética , Recombinação Genética/efeitos dos fármacos , Reprodutibilidade dos Testes , Ativação Transcricional/efeitos dos fármacos , Transfecção/métodos , Transgenes/genética
7.
Anal Bioanal Chem ; 412(28): 7685-7699, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870351

RESUMO

Pathogen-host cell interactions play an important role in many human infectious and inflammatory diseases. Several pathogens, including Escherichia coli (E. coli), Mycobacterium tuberculosis (M. tb), and even the recent 2019 novel coronavirus (2019-nCoV), can cause serious breathing and brain disorders, tissue injury and inflammation, leading to high rates of mortality and resulting in great loss to human physical and mental health as well as the global economy. These infectious diseases exploit the microbial and host factors to induce serious inflammatory and immunological symptoms. Thus the development of anti-inflammatory drugs targeting bacterial/viral infection is an urgent need. In previous studies, YojI-IFNAR2, YojI-IL10RA, YojI-NRP1,YojI-SIGLEC7, and YojI-MC4R membrane-protein interactions were found to mediate E. coli invasion of the blood-brain barrier (BBB), which activated the downstream anti-inflammatory proteins NACHT, LRR and PYD domains-containing protein 2(NLRP2), using a proteomic chip conjugated with cell immunofluorescence labeling. However, the studies of pathogen (bacteria/virus)-host cell interactions mediated by membrane protein interactions did not extend their principles to broad biomedical applications such as 2019-nCoV infectious disease therapy. The first part of this feature article presents in-depth analysis of the cross-talk of cellular anti-inflammatory transduction signaling among interferon membrane protein receptor II (IFNAR2), interleukin-10 receptor subunit alpha (IL-10RA), NLRP2 and [Ca2+]-dependent phospholipase A2 (PLA2G5), based on experimental results and important published studies, which lays a theoretical foundation for the high-throughput construction of the cytokine and virion solution chip. The paper then moves on to the construction of the novel GPCR recombinant herpes virion chip and virion nano-oscillators for profiling membrane protein functions, which drove the idea of constructing the new recombinant virion and cytokine liquid chips for HTS of leading drugs. Due to the different structural properties of GPCR, IFNAR2, ACE2 and Spike of 2019-nCoV, their ligands will either bind the extracellular domain of IFNAR2/ACE2/Spike or the specific loops of the GPCR on the envelope of the recombinant herpes virions to induce dynamic charge distribution changes that lead to the variable electron transition for detection. Taken together, the combined overview of two of the most innovative and exciting developments in the immunoinflammatory field provides new insight into high-throughput construction of ultrasensitive cytokine and virion liquid chips for HTS of anti-inflammatory drugs or clinical diagnosis and treatment of inflammatory diseases including infectious diseases, acute or chronic inflammation (acute gouty arthritis or rheumatoid arthritis), cardiovascular disease, atheromatosis, diabetes, obesity, tissue injury and tumors. It has significant value in the prevention and treatment of these serious and painful diseases. Graphical abstract.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Ensaios de Triagem em Larga Escala/instrumentação , Dispositivos Lab-On-A-Chip , Testes de Sensibilidade Microbiana/instrumentação , Animais , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Descoberta de Drogas/instrumentação , Descoberta de Drogas/métodos , Desenho de Equipamento , Ensaios de Triagem em Larga Escala/métodos , Humanos , Testes de Sensibilidade Microbiana/métodos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Bibliotecas de Moléculas Pequenas/farmacologia , Vírion/efeitos dos fármacos , Vírion/imunologia , Viroses/tratamento farmacológico , Viroses/imunologia
8.
Clin Epigenetics ; 12(1): 118, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758273

RESUMO

Coronaviruses (CoVs) are highly diverse single-stranded RNA viruses owing to their susceptibility to numerous genomic mutations and recombination. Such viruses involve human and animal pathogens including the etiologic agents of acute respiratory tract illnesses: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the highly morbific SARS-CoV-2. Coronavirus disease 2019 (COVID-19), an emerging disease with a quick rise in infected cases and deaths, was recently identified causing a worldwide pandemic. COVID-19 disease outcomes were found to increase in elderly and patients with a compromised immune system. Evidences indicated that the main culprit behind COVID-19 deaths is the cytokine storm, which is illustrated by an uncontrolled over-production of soluble markers of inflammation. The regulation process of coronavirus pathogenesis through molecular mechanism comprise virus-host interactions linked to viral entry, replication and transcription, escape, and immune system control. Recognizing coronavirus infections and COVID-19 through epigenetics lens will lead to potential alteration in gene expression thus limiting coronavirus infections. Focusing on epigenetic therapies reaching clinical trials, clinically approved epigenetic-targeted agents, and combination therapy of antivirals and epigenetic drugs is currently considered an effective and valuable approach for viral replication and inflammatory overdrive control.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Epigenômica/métodos , Pandemias , Pneumonia Viral , Betacoronavirus/genética , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Genoma Viral/efeitos dos fármacos , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia
9.
Nat Commun ; 11(1): 4200, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826910

RESUMO

Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in the development of optimized small-molecule compounds. Current approaches cannot identify the protein targets of a compound and also detect the interaction surfaces between ligands and protein targets without prior labeling or modification. To address this limitation, we here develop LiP-Quant, a drug target deconvolution pipeline based on limited proteolysis coupled with mass spectrometry that works across species, including in human cells. We use machine learning to discern features indicative of drug binding and integrate them into a single score to identify protein targets of small molecules and approximate their binding sites. We demonstrate drug target identification across compound classes, including drugs targeting kinases, phosphatases and membrane proteins. LiP-Quant estimates the half maximal effective concentration of compound binding sites in whole cell lysates, correctly discriminating drug binding to homologous proteins and identifying the so far unknown targets of a fungicide research compound.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Aprendizado de Máquina , Proteoma , Proteômica/métodos , Sítios de Ligação , Botrytis , Sobrevivência Celular , Biologia Computacional/métodos , Descoberta de Drogas/métodos , Células HeLa , Humanos , Ligantes , Espectrometria de Massas , Fosfotransferases/metabolismo , Ligação Proteica , Proteólise , Saccharomyces cerevisiae
10.
Chem Biol Interact ; 330: 109244, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32861748

RESUMO

The 2-aminothiazole functionality has long been established as a privileged structural feature and therefore frequently exploited in the process of drug discovery and development. It has been introduced into numerous compounds due to its capacity for targeting a wide range of therapeutic target proteins. On the other hand, the aminothiazole group has also been classified as a toxicophore susceptible to metabolic activation and the ensuing reactive metabolite formation, hence caution is warranted when used in drug design. This review is divided into three parts entailing: (i) the general characteristics of the aminothiazole group, (ii) the advantages of the aminothiazole group in medicinal chemistry, and (iii) the impact of the integrated aminothiazole group on compound safety profile.


Assuntos
Descoberta de Drogas/métodos , Tiazóis/química , Animais , Humanos , Relação Estrutura-Atividade , Tiazóis/metabolismo , Tiazóis/toxicidade
11.
Eur J Pharmacol ; 884: 173455, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32745604

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that uses the human angiotensin-converting enzyme 2 (ACE2) receptor as a point of entry. The present review discusses the origin and structure of the virus and its mechanism of cell entry followed by the therapeutic potentials of strategies directed towards SARS-CoV2-ACE2 binding, the renin-angiotensin system, and the kinin-kallikrein system. SARS-CoV2-ACE2 binding-directed approaches mainly consist of targeting receptor binding domain, ACE2 blockers, soluble ACE2, and host protease inhibitors. In conclusion, blocking or manipulating the SARS-CoV2-ACE2 binding interface perhaps offers the best tactic against the virus that should be treated as a fundamental subject of future research.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus , Descoberta de Drogas/métodos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Receptores Virais/metabolismo
12.
Acta Pharmacol Sin ; 41(9): 1141-1149, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32747721

RESUMO

Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
13.
PLoS One ; 15(8): e0237181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813697

RESUMO

Multidrug-resistant Vibrio parahaemolyticus has become a significant public health concern. The development of effective drugs and vaccines against Vibrio parahaemolyticus is the current research priority. Thus, we aimed to find out effective drug and vaccine targets using a comprehensive genome-based analysis. A total of 4822 proteins were screened from V. parahaemolyticus proteome. Among 16 novel cytoplasmic proteins, 'VIBPA Type II secretion system protein L' and 'VIBPA Putative fimbrial protein Z' were subjected to molecular docking with 350 human metabolites, which revealed that Eliglustat, Simvastatin and Hydroxocobalamin were the top drug molecules considering free binding energy. On the contrary, 'Sensor histidine protein kinase UhpB' and 'Flagellar hook-associated protein of 25 novel membrane proteins were subjected to T-cell and B-cell epitope prediction, antigenicity testing, transmembrane topology screening, allergenicity and toxicity assessment, population coverage analysis and molecular docking analysis to generate the most immunogenic epitopes. Three subunit vaccines were constructed by the combination of highly antigenic epitopes along with suitable adjuvant, PADRE sequence and linkers. The designed vaccine constructs (V1, V2, V3) were analyzed by their physiochemical properties and molecular docking with MHC molecules- results suggested that the V1 is superior. Besides, the binding affinity of human TLR-1/2 heterodimer and construct V1 could be biologically significant in the development of the vaccine repertoire. The vaccine-receptor complex exhibited deformability at a minimum level that also strengthened our prediction. The optimized codons of the designed construct was cloned into pET28a(+) vector of E. coli strain K12. However, the predicted drug molecules and vaccine constructs could be further studied using model animals to combat V. parahaemolyticus associated infections.


Assuntos
Vacinas Bacterianas/imunologia , Descoberta de Drogas/métodos , Genoma Bacteriano , Vibrioses/tratamento farmacológico , Vibrioses/prevenção & controle , Vibrio parahaemolyticus/genética , Vibrio parahaemolyticus/imunologia , Biologia Computacional/métodos , Farmacorresistência Bacteriana Múltipla/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Escherichia coli K12/genética , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mapas de Interação de Proteínas , Proteoma/genética , Proteômica/métodos , Vacinas de Subunidades/imunologia , Vibrioses/microbiologia
14.
Exp Cell Res ; 395(2): 112204, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735892

RESUMO

BACKGROUND: SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach. METHODS: In the present investigation, we evaluated the effects of SARS-CoV2 on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV2 potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analyzed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV2, SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses. RESULTS: The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV2 and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV2 infection. CONCLUSIONS: Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment.


Assuntos
Brônquios/metabolismo , Infecções por Coronavirus/genética , Redes Reguladoras de Genes , Pneumonia Viral/genética , Mucosa Respiratória/metabolismo , Transcriptoma , Brônquios/patologia , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Dineínas/genética , Dineínas/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Imunidade Inata , Aprendizado de Máquina , Pandemias , Pneumonia Viral/metabolismo , Regulação para Cima
15.
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
16.
Theranostics ; 10(16): 7034-7052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32641977

RESUMO

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/isolamento & purificação , Vacinas Virais/farmacologia , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/imunologia , Bioengenharia/métodos , Bioengenharia/tendências , Reatores Biológicos , Técnicas de Cultura de Células , Simulação por Computador , Infecções por Coronavirus/imunologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Avaliação de Medicamentos/métodos , Avaliação de Medicamentos/tendências , Farmacorresistência Viral , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Modelos Biológicos , Organoides/citologia , Organoides/virologia , Pneumonia Viral/imunologia , Nanomedicina Teranóstica
17.
Eur J Pharmacol ; 883: 173348, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634438

RESUMO

The global pandemic of coronavirus disease 2019 (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 7,273,958 cases with almost over 413,372 deaths worldwide as per the WHO situational report 143 on COVID-19. There are no known treatment regimens with proven efficacy and vaccines thus far, posing an unprecedented challenge to identify effective drugs and vaccines for prevention and treatment. The urgency for its prevention and cure has resulted in an increased number of proposed treatment options. The high rate and volume of emerging clinical trials on therapies for COVID-19 need to be compared and evaluated to provide scientific evidence for effective medical options. Other emerging non-conventional drug discovery techniques such as bioinformatics and cheminformatics, structure-based drug design, network-based methods for prediction of drug-target interactions, artificial intelligence (AI) and machine learning (ML) and phage technique could provide alternative routes to discovering potent Anti-SARS-CoV2 drugs. While drugs are being repurposed and discovered for COVID-19, novel drug delivery systems will be paramount for efficient delivery and avoidance of possible drug resistance. This review describes the proposed drug targets for therapy, and outcomes of clinical trials that have been reported. It also identifies the adopted treatment modalities that are showing promise, and those that have failed as drug candidates. It further highlights various emerging therapies and future strategies for the treatment of COVID-19 and delivery of Anti-SARS-CoV2 drugs.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Pandemias , Pneumonia Viral , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle
18.
Ann Am Thorac Soc ; 17(10): 1186-1194, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32692580

RESUMO

The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist; thus, development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and antiinflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date, only dexamethasone and remdesivir have been shown to be effective, but several other promising candidates are in trials.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Fatores Imunológicos/farmacologia , Pandemias , Pneumonia Viral , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Seleção de Pacientes , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia
19.
Proc Natl Acad Sci U S A ; 117(31): 18744-18753, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32680963

RESUMO

Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here we utilized the cell-to-cell variation in morphological features of Mycobacterium tuberculosis bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding of Stress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target activities. We observed cell wall damage induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of cellular damage in tubercle bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas/métodos , Mycobacterium tuberculosis , Software , Parede Celular/efeitos dos fármacos , Diarilquinolinas , Ensaios de Triagem em Larga Escala , Mycobacterium tuberculosis/citologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Transcriptoma/efeitos dos fármacos
20.
BMC Bioinformatics ; 21(1): 330, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703151

RESUMO

BACKGROUND: Drugs achieve pharmacological functions by acting on target proteins. Identifying interactions between drugs and target proteins is an essential task in old drug repositioning and new drug discovery. To recommend new drug candidates and reposition existing drugs, computational approaches are commonly adopted. Compared with the wet-lab experiments, the computational approaches have lower cost for drug discovery and provides effective guidance in the subsequent experimental verification. How to integrate different types of biological data and handle the sparsity of drug-target interaction data are still great challenges. RESULTS: In this paper, we propose a novel drug-target interactions (DTIs) prediction method incorporating marginalized denoising model on heterogeneous networks with association index kernel matrix and latent global association. The experimental results on benchmark datasets and new compiled datasets indicate that compared to other existing methods, our method achieves higher scores of AUC (area under curve of receiver operating characteristic) and larger values of AUPR (area under precision-recall curve). CONCLUSIONS: The performance improvement in our method depends on the association index kernel matrix and the latent global association. The association index kernel matrix calculates the sharing relationship between drugs and targets. The latent global associations address the false positive issue caused by network link sparsity. Our method can provide a useful approach to recommend new drug candidates and reposition existing drugs.


Assuntos
Descoberta de Drogas/métodos , Biologia Computacional/métodos , Reposicionamento de Medicamentos , Proteínas/efeitos dos fármacos , Curva ROC
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