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1.
Nat Commun ; 11(1): 5485, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127883

RESUMO

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Aprendizado de Máquina , Organoides/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Desenvolvimento de Medicamentos/métodos , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Organoides/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transcriptoma , Bexiga Urinária/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
2.
Int J Med Sci ; 17(16): 2511-2530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029094

RESUMO

ShuFeng JieDu capsule (SFJDC), a traditional Chinese medicine, has been recommended for the treatment of COVID-19 infections. However, the pharmacological mechanism of SFJDC still remains vague to date. The active ingredients and their target genes of SFJDC were collected from TCMSP. COVID-19 is a type of Novel Coronavirus Pneumonia (NCP). NCP-related target genes were collected from GeneCards database. The ingredients-targets network of SFJDC and PPI networks were constructed. The candidate genes were screened by Venn diagram package for enrichment analysis. The gene-pathway network was structured to obtain key target genes. In total, 124 active ingredients, 120 target genes of SFJDC and 251 NCP-related target genes were collected. The functional annotations cluster 1 of 23 candidate genes (CGs) were related to lung and Virus infection. RELA, MAPK1, MAPK14, CASP3, CASP8 and IL6 were the key target genes. The results suggested that SFJDC cloud be treated COVID-19 by multi-compounds and multi-pathways, and this study showed that the mechanism of traditional Chinese medicine (TCM) in the treatment of disease from the overall perspective.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Pneumonia Viral/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Antivirais/química , Cápsulas/farmacologia , Caspase 3/genética , Caspase 8/genética , Infecções por Coronavirus/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Pandemias , Pneumonia Viral/genética , Mapas de Interação de Proteínas/genética , Fator de Transcrição RelA/genética
3.
Viruses ; 12(10)2020 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993136

RESUMO

In a short time, the COVID-19 pandemic has left the world with over 25 million cases and staggering death tolls that are still rising. Treatments for SARS-CoV-2 infection are desperately needed as there are currently no approved drug therapies. With limited knowledge of viral mechanisms, a network controllability method of prioritizing existing drugs for repurposing efforts is optimal for quickly moving through the drug approval pipeline using limited, available, virus-specific data. Based on network topology and controllability, 16 proteins involved in translation, cellular transport, cellular stress, and host immune response are predicted as regulators of the SARS-CoV-2 infected cell. Of the 16, eight are prioritized as possible drug targets where two, PVR and SCARB1, are previously unexplored. Known compounds targeting these genes are suggested for viral inhibition study. Prioritized proteins in agreement with previous analysis and viral inhibition studies verify the ability of network controllability to predict biologically relevant candidates.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Aprovação de Drogas , Sistemas de Liberação de Medicamentos , Interações Hospedeiro-Patógeno , Humanos , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Receptores Virais/genética , Receptores Virais/metabolismo , Receptores Depuradores Classe B/metabolismo , Integração Viral
4.
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
5.
J Chem Inf Model ; 60(8): 3910-3934, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32786511

RESUMO

Protein-protein interactions (PPIs) are attractive targets for drug design because of their essential role in numerous cellular processes and disease pathways. However, in general, PPIs display exposed binding pockets at the interface, and as such, have been largely unexploited for therapeutic interventions with low-molecular weight compounds. Here, we used docking and various rescoring strategies in an attempt to recover PPI inhibitors from a set of active and inactive molecules for 11 targets collected in ChEMBL and PubChem. Our focus is on the screening power of the various developed protocols and on using fast approaches so as to be able to apply such a strategy to the screening of ultralarge libraries in the future. First, we docked compounds into each target using the fast "pscreen" mode of the structure-based virtual screening (VS) package Surflex. Subsequently, the docking poses were postprocessed to derive a set of 3D topological descriptors: (i) shape similarity and (ii) interaction fingerprint similarity with a co-crystallized inhibitor, (iii) solvent-accessible surface area, and (iv) extent of deviation from the geometric center of a reference inhibitor. The derivatized descriptors, together with descriptor-scaled scoring functions, were utilized to investigate possible impacts on VS performance metrics. Moreover, four standalone scoring functions, RF-Score-VS (machine-learning), DLIGAND2 (knowledge-based), Vinardo (empirical), and X-SCORE (empirical), were employed to rescore the PPI compounds. Collectively, the results indicate that the topological scoring algorithms could be valuable both at a global level, with up to 79% increase in areas under the receiver operating characteristic curve for some targets, and in early stages, with up to a 4-fold increase in enrichment factors at 1% of the screened collections. Outstandingly, DLIGAND2 emerged as the best scoring function on this data set, outperforming all rescoring techniques in terms of VS metrics. The described methodology could help in the rational design of small-molecule PPI inhibitors and has direct applications in many therapeutic areas, including cancer, CNS, and infectious diseases such as COVID-19.


Assuntos
Desenho de Fármacos , Descoberta de Drogas , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Algoritmos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Bases de Dados de Proteínas , Humanos , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Proteínas/química , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas/química
6.
PLoS One ; 15(8): e0237845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813721

RESUMO

Aluminum (Al3+) toxicity is one of the most important limitations to agricultural production worldwide. The overall response of plants to Al3+ stress has been documented, but the contribution of protein phosphorylation to Al3+ detoxicity and tolerance in plants is unclear. Using a combination of tandem mass tag (TMT) labeling, immobilized metal affinity chromatography (IMAC) enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS), Al3+-induced phosphoproteomic changes in roots of Tamba black soybean (TBS) were investigated in this study. The Data collected in this study are available via ProteomeXchange with the identifier PXD019807. After the Al3+ treatment, 189 proteins harboring 278 phosphosites were significantly changed (fold change > 1.2 or < 0.83, p < 0.05), with 88 upregulated, 96 downregulated and 5 up-/downregulated. Enrichment and protein interaction analyses revealed that differentially phosphorylated proteins (DPPs) under the Al3+ treatment were mainly related to G-protein-mediated signaling, transcription and translation, transporters and carbohydrate metabolism. Particularly, DPPs associated with root growth inhibition or citric acid synthesis were identified. The results of this study provide novel insights into the molecular mechanisms of TBS post-translational modifications in response to Al3+ stress.


Assuntos
Alumínio/toxicidade , Fosfoproteínas/metabolismo , Proteínas de Plantas/metabolismo , Proteômica , Soja/metabolismo , Citratos/metabolismo , Fosforilação/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Soja/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
7.
Life Sci ; 257: 118096, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679150

RESUMO

AIMS: The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19. MATERIALS AND METHODS: The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations. KEY FINDINGS: A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs. SIGNIFICANCE: The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/metabolismo , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Antivirais/uso terapêutico , Betacoronavirus/metabolismo , Betacoronavirus/patogenicidade , Cloroquina/farmacologia , Biologia Computacional/métodos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Melatonina/farmacologia , Metaloproteases/metabolismo , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/fisiopatologia , Transporte Proteico
8.
PLoS One ; 15(7): e0236441, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701973

RESUMO

Biofilms are microbial communities embedded in an extracellular polymeric matrix and display an enhanced tolerance to the action of antimicrobials. The emergence of novel functionalised nanoparticles is considered a promising avenue for the development of biofilm-specific antimicrobial technologies. However, there is a gap in the understanding of interactions between nanoparticles and the biofilm matrix. Particularly, questions are raised on how nanoparticle charge and surface groups play a role in aggregation when in contact with biofilm components. Herein we present the synthesis of four types of silica nanoparticles and undertake an analysis of their interactions with Pseudomonas fluorescens biofilm matrix. The effect of the biofilm matrix components on the charge and aggregation of the nanoparticles was assessed. Additionally, the study focused on the role of matrix proteins, with the in-depth characterisation of the protein corona of each nanoparticle by Liquid Chromatography with Tandem Mass Spectrometry experiments. The protein corona composition is dependent on the nanoparticle type; non-functionalised nanoparticles show less protein selectivity, whereas carboxylate-functionalised nanoparticles prefer proteins with a higher isoelectric point. These outcomes provide insights into the field of biofilm-nanoparticle interactions that can be valuable for the design of new nano-based targeting systems in future anti-biofilm applications.


Assuntos
Biofilmes/efeitos dos fármacos , Nanopartículas Metálicas/química , Pseudomonas fluorescens/efeitos dos fármacos , Dióxido de Silício/farmacologia , Biofilmes/crescimento & desenvolvimento , Cromatografia Líquida , Humanos , Coroa de Proteína/química , Mapas de Interação de Proteínas/efeitos dos fármacos , Pseudomonas fluorescens/crescimento & desenvolvimento , Dióxido de Silício/química , Espectrometria de Massas em Tandem
9.
PLoS One ; 15(6): e0235118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579601

RESUMO

During diabetes, renal proximal tubular cells (PTC) are exposed to a combination of high glucose and hypoxic conditions, which plays a relevant role in the development of diabetic kidney disease (DKD). In this work, a time-series proteomic study was performed to analyse the effect of a diabetic-like microenvironment induced changes on HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions for up to 48 h. Diabetic conditions increased the percentage of death cells after 24 and 48 h, but no differences in the protein/cell ratio were found. The relative protein quantification using dimethyl-labeling and UHPLC-MS/MS analysis allowed the identification of 317, 296 and 259 proteins at 5, 24 and 48 h, respectively. The combination of statistical and time expression profile analyses indicated an increased expression of proteins involved in glycolysis, and a decrease of cytoskeletal-related proteins. The exposure of HK-2 cells to high glucose and hypoxia reproduces some of the effects of diabetes on PTC and, with the limitations inherent to in vitro studies, propose new mechanisms and targets to be considered in the management of DKD.


Assuntos
Células Epiteliais/metabolismo , Glucose/metabolismo , Túbulos Renais Proximais/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Hipóxia Celular , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Nefropatias Diabéticas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
10.
Protein J ; 39(3): 198-216, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-342993

RESUMO

The devastating effects of the recent global pandemic (termed COVID-19 for "coronavirus disease 2019") caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) are paramount with new cases and deaths growing at an exponential rate. In order to provide a better understanding of SARS CoV-2, this article will review the proteins found in the SARS CoV-2 that caused this global pandemic.


Assuntos
Betacoronavirus/química , Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Genoma Viral , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais Reguladoras e Acessórias/química , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo
11.
Nat Commun ; 11(1): 2376, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398747

RESUMO

Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.


Assuntos
Citoproteção/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular , Citoproteção/fisiologia , Regulação da Expressão Gênica/fisiologia , Técnicas de Inativação de Genes , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/isolamento & purificação , Ácido Hialurônico/metabolismo , Longevidade/fisiologia , Camundongos , Ratos-Toupeira/fisiologia , Peso Molecular , Cultura Primária de Células , Mapas de Interação de Proteínas/efeitos dos fármacos , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Especificidade da Espécie , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Protein J ; 39(3): 198-216, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32447571

RESUMO

The devastating effects of the recent global pandemic (termed COVID-19 for "coronavirus disease 2019") caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) are paramount with new cases and deaths growing at an exponential rate. In order to provide a better understanding of SARS CoV-2, this article will review the proteins found in the SARS CoV-2 that caused this global pandemic.


Assuntos
Betacoronavirus/química , Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Betacoronavirus/genética , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Genoma Viral , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais Reguladoras e Acessórias/química , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo
13.
Biochem Biophys Res Commun ; 525(2): 520-527, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32113678

RESUMO

Extremely high relapse rate is the dramatic challenge of drug abuse at present. Environmental cues play an important role in relapse of drug abuse. However, the specific mechanism underlying relapse remains unclear. Using morphine conditioned place preference (CPP) model, we show that association of neuronal nitric oxide synthase (nNOS) with postsynaptic density-95 (PSD-95) plays a significant role in morphine priming-induced reinstatement. The nNOS-PSD-95 coupling and c-Fos expression in the medial prefrontal cortex (mPFC) was significantly increased after extinction of morphine CPP. Dissociation of nNOS-PSD-95 in the mPFC by ZL006 inhibited the reinstatement of morphine CPP induced by a priming dose of morphine. Significantly reduced phosphorylation of cAMP-response element binding protein (CREB) in the mPFC was observed in the mice exposed to morphine after the extinction training. Uncoupling nNOS-PSD-95 reversed the morphine-induced CREB dysfunction. Moreover, effects of ZL006 on the reinstatement of morphine CPP and CREB activation depended on nNOS-PSD-95 target. Together, our findings suggest that nNOS-PSD-95 in the mPFC contributes to reinstatement of morphine CPP, possibly through CREB dysfunction, offering a potential target to prevent relapse of drug abuse.


Assuntos
Proteína 4 Homóloga a Disks-Large/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos
14.
PLoS One ; 15(3): e0226883, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191711

RESUMO

We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either ribosomal proteins, ubiquitination pathway proteins or heat shock proteins. We propose some of the proteins identified in this study to be considered for drug targeting.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Medicina de Precisão/métodos , Mapas de Interação de Proteínas/imunologia , Transdução de Sinais/imunologia , Biologia Computacional , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/imunologia , Proteínas de Choque Térmico/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Ribossômicas/antagonistas & inibidores , Proteínas Ribossômicas/imunologia , Proteínas Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos
15.
J Med Chem ; 63(6): 2802-2806, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32157887

RESUMO

Heterobifunctional molecules, which recruit E3 ligases to ubiquitinate a target protein of interest, have found wide application as both biological tools and molecules with the potential to have clinical effects. In their recent paper, Yamazoe et al. report a heterobifunctional molecule that recruits the phosphatase PP1 to promote the dephosphorylation of pAKT to give AKT. This Viewpoint seeks to place this work in the wider context of heterobifunctional molecules and looks ahead to new possibilities presented by these results.


Assuntos
Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Descoberta de Drogas , Humanos , Ligantes , Complexo de Endopeptidases do Proteassoma/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos
16.
Proc Natl Acad Sci U S A ; 117(11): 6121-6128, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123072

RESUMO

Virus replication requires critical interactions between viral proteins and cellular proteins that mediate many aspects of infection, including the transport of viral genomes to the site of replication. In human papillomavirus (HPV) infection, the cellular protein complex known as retromer binds to the L2 capsid protein and sorts incoming virions into the retrograde transport pathway for trafficking to the nucleus. Here, we show that short synthetic peptides containing the HPV16 L2 retromer-binding site and a cell-penetrating sequence enter cells, sequester retromer from the incoming HPV pseudovirus, and inhibit HPV exit from the endosome, resulting in loss of viral components from cells and in a profound, dose-dependent block to infection. The peptide also inhibits cervicovaginal HPV16 pseudovirus infection in a mouse model. These results confirm the retromer-mediated model of retrograde HPV entry and validate intracellular virus trafficking as an antiviral target. More generally, inhibiting virus replication with agents that can enter cells and disrupt essential protein-protein interactions may be applicable in broad outline to many viruses.


Assuntos
Proteínas do Capsídeo/metabolismo , Peptídeos Penetradores de Células/farmacologia , Papillomavirus Humano 16/efeitos dos fármacos , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Animais , Peptídeos Penetradores de Células/uso terapêutico , Colo do Útero/virologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Células HeLa , Papillomavirus Humano 16/fisiologia , Humanos , Camundongos , Infecções por Papillomavirus/virologia , Ligação Proteica/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Vagina/virologia
17.
Sci Rep ; 10(1): 2658, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060346

RESUMO

The neurovascular unit, which includes neurons, glial cells, and vascular cells, plays crucial roles in the onset and progression of Alzheimer's disease (AD). Therefore, effective drugs against AD should be able to target the multi-cellular neurovascular unit and the therapeutic relationships among neurovascular cells should be defined. Here, we examined the therapeutic effects of Ukgansan (UGS), an herbal remedy with multi-targeting capabilities, using in vitro neurovascular unit models and an in vivo model of AD. In addition, we compared the therapeutic networks induced by UGS and its components in different neurovascular cell types. We found that UGS and its components protected neurovascular cells against diverse damaging agents and improved the behavioral patterns of AD model mice. A comparison of UGS- or its components-induced therapeutic networks, constructed from high-throughput data on gene expression, pathway activity, and protein phosphorylation, revealed similarities among neurovascular cell types, especially between BV-2 microglia and HBVP (human brain vascular pericytes). These findings, together with the functional connections between neurovascular cells, can explain the therapeutic effects of UGS. Furthermore, they suggest underlying similarities in the therapeutic mechanisms in different neurovascular cell types.


Assuntos
Medicina Tradicional do Leste Asiático , Neurônios/citologia , Doença de Alzheimer/tratamento farmacológico , Animais , Linhagem Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Camundongos , Fosforilação , Mapas de Interação de Proteínas/efeitos dos fármacos
18.
DNA Cell Biol ; 39(5): 836-847, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32101033

RESUMO

Prostate cancer (PCa) is a common malignant tumor in elderly men worldwide. Most primary PCas inevitably progress into castration-resistant prostate cancer (CRPC) after androgen deprivation therapy. The mechanisms contributing to this progression are still controversial. In this study, functional module genes, DNA methylations, core regulators, and potential drugs in primary PCa and CRPC were explored by integrating a series of bioinformatics analyses. First, 588 differentially expressed genes (DEGs) were identified. Combined with related genes, protein-protein interaction networks were constructed, and 22 and 14 significant modules were identified in primary PCa and CRPC, respectively. More DEGs were identified in differentially methylated genes in CRPC modules. The hub genes in CRPC included CDC20 and CDK1. Moreover, core noncoding RNAs and transcription factors that significantly regulate CRPC modules were identified, including TUG1, MALAT1, E2F3, and MED1. Finally, the prediction of potential drugs for primary PCa and CRPC was also performed. Exisulind and phosphodiesterase-4 inhibitors were predicted as potential drugs for CRPC. The results of this study provide a new way for biologists and pharmacists to understand the potential molecular mechanisms of CRPC and also provide valuable references for drug redirection and new drug development for PCa.


Assuntos
Biologia Computacional , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Fatores de Transcrição/genética
19.
J Med Chem ; 63(5): 2588-2619, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32037829

RESUMO

Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Proteína BRCA2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Rad51 Recombinase/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos/química , Proteína BRCA2/genética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Descoberta de Drogas , Sinergismo Farmacológico , Recombinação Homóloga/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ftalazinas/química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Mutações Sintéticas Letais/efeitos dos fármacos
20.
Cell Mol Life Sci ; 77(23): 4997-5015, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31974654

RESUMO

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the recessive genetic disease cystic fibrosis, where the chloride transport across the apical membrane of epithelial cells mediated by the CFTR protein is impaired. CFTR protein trafficking to the plasma membrane (PM) is the result of a complex interplay between the secretory and membrane recycling pathways that control the number of channels present at the membrane. In addition, the ion transport activity of CFTR at the PM is modulated through post-translational protein modifications. Previously we described that spleen tyrosine kinase (SYK) phosphorylates a specific tyrosine residue in the nucleotide-binding domain 1 domain and this modification can regulate the PM abundance of CFTR. Here we identified the underlying biochemical mechanism using peptide pull-down assays followed by mass spectrometry. We identified in bronchial epithelial cells that the adaptor protein SHC1 recognizes tyrosine-phosphorylated CFTR through its phosphotyrosine-binding domain and that the formation of a complex between SHC1 and CFTR is induced at the PM in the presence of activated SYK. The depletion of endogenous SHC1 expression was sufficient to promote an increase in CFTR at the PM of these cells. The results identify a SYK/SHC1 pathway that regulates the PM levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated.


Assuntos
Membrana Celular/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Quinase Syk/metabolismo , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Cloretos/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/patologia , Fosfopeptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Mapas de Interação de Proteínas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinase Syk/antagonistas & inibidores
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