RESUMEN
The outbreak of severe pneumonia at the end of 2019 was proved to be caused by the SARS-CoV-2 virus spreading out the world. And COVID-19 spread rapidly through a terrible transmission way by human-to-human, which led to many suspected cases waiting to be diagnosed and huge daily samples needed to be tested by an effective and rapid detection method. With an increasing number of COVID-19 infections, medical pressure is severe. Therefore, more efficient and accurate diagnosis methods were keen urgently established. In this review, we summarized several methods that can rapidly and sensitively identify COVID-19; some of them are widely used as the diagnostic techniques for SARS-CoV-2 in various countries, some diagnostic technologies refer to SARS (Severe Acute Respiratory Syndrome) or/and MERS (Middle East Respiratory Syndrome) detection, which may provide potential diagnosis ideas.
RESUMEN
Free Fatty Acid 4 receptor (FFA4 receptor or GPR120), a rhodopsin-like G protein coupled receptor (GPCR) subfamily member, is a receptor that senses specific fatty acids such as ω-3 fatty acid in fish oil or the endogenous signaling lipid, PHASA. FFA4 receptor is enriched in lung, colon and adipose tissue but is also detected in many other tissues and cells. The activation of FFA4 receptor has multiple effects, including but not limited to inhibition of inflammation, improving insulin sensitivity and adipogenesis, and regulating hormone secretion from the gastro-intestinal system and pancreatic islets. The important role of FFA4 receptor in maintaining metabolic homeostasis strongly indicates the great potential of selective FFA4 receptor agonizts to treat diabetes and inflammation. In this review, we summarize recent research progress in the physiological and biochemical studies of FFA4 receptor and highlight its underlying signaling mechanisms and ligand identification to assist future research to exploit FFA4 receptor as a drug target.
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Descubrimiento de Drogas/métodos , Hipoglucemiantes/farmacología , Terapia Molecular Dirigida/métodos , Receptores Acoplados a Proteínas G/metabolismo , Secuencia de Aminoácidos , Animales , Arrestina/metabolismo , Humanos , Datos de Secuencia Molecular , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward para-nitrophenyl phosphate, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both kinase interaction motif (KIM) and kinase-specific sequence of STEP were required for ERK interaction. In addition to the N-terminal kinase-specific sequence region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders. Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor.
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Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Secuencia de Aminoácidos , Animales , Dominio Catalítico , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Células PC12 , Fosforilación , Proteínas Tirosina Fosfatasas no Receptoras/genética , RatasRESUMEN
Protein phosphorylation is an important post-translational modification that regulates almost every aspect of signal transduction in cells. Activation of the mitogen-activated protein kinase (MAPK) family kinase extracellular signal-regulated kinase (ERK) is a point of convergence for many cellular activities in response to external stimulation. With stimuli, ERK activity is significantly increased by the phosphorylation of Thr202 and Tyr204 at its activation loop. Downregulation of ERK phosphorylation at these two sites by several phosphatases, such as protein phosphatase 2A, HePTP and MAPK phosphatase 3, is essential for maintaining appropriate ERK function in different cellular processes. However, it is unknown whether metal-dependent protein phosphatase (PPM) family phosphatases directly dephosphorylate ERK. In this study, we found that PPM1A negatively regulated ERK by directly dephosphorylating its pThr202 position early in EGF stimulation. Additional kinetic studies revealed that key residues participated in phospho-ERK recognition by PPM1A. Importantly, PPM1A preferred the phospho-ERK peptide sequence over a panel of other phosphopeptides through the interactions of basic residues in the active site of PPM1A with the pThr-Glu-pTyr motif of ERK. Whereas Lys165 and Arg33 were required for efficient catalysis or phosphosubstrate binding of PPM1A, Gln185 and Arg186 were determinants of PPM1A substrate specificity. The interaction between Arg186 of PPM1A and Glu203 and pTyr204 of phospho-ERK was identified as a hot-spot for phospho-ERK-PPM1A interaction.
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Quinasas MAP Reguladas por Señal Extracelular/fisiología , Fosfoproteínas Fosfatasas/fisiología , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Factor de Crecimiento Epidérmico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Mutagénesis Sitio-Dirigida , Fosfoproteínas Fosfatasas/química , Fosfoproteínas Fosfatasas/genética , Fosforilación/genética , Proteína Fosfatasa 2C , Especificidad por Sustrato/genéticaRESUMEN
Phenyl-piperazines were designed and synthesized based on pharmacophore for uro-selective alpha(1)-adrenoceptor antagonists and 3D chemical database searching. Within this series, three compounds, 2, 3, and 13, showed similar or better alpha(1)-AR antagonistic activity compared with prazosin. The 3D-QSAR study of these compounds may provide useful information for the development of novel aryl-piperazines as uro-selective alpha(1)-adrenoceptor antagonists, which can be used for the treatment of BPH with fewer side effects.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntesis química , Diseño de Fármacos , Piperazinas/síntesis química , Relación Estructura-Actividad Cuantitativa , Antagonistas Adrenérgicos alfa/farmacología , Bases de Datos Factuales , Humanos , Masculino , Piperazinas/farmacología , Prazosina , Hiperplasia Prostática/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
This investigation was performed to assess the importance of interaction in the binding of blockers to KCNQ1 potassium using molecular modeling. This work could be considered made up by three main steps: (1) the construction of closed-state structure of KCNQ1 through homology modeling; (2) the automated docking of three blockers: IKS-142, L-735821, and BMS-IKS, using DOCK program; (3) the generation and validation of pharmacophore for KCNQ1 ligands using Catalyst/HypoGen. The obtained results highlight the hydrophobic or aromatic residues involved in S6 transmembrane domain and the base of the pore helix of KCNQ1, confirming the mutagenesis data and pharmacophore model, and giving new suggestions for the rational design of novel KCNQ1 ligands.
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Canales de Potasio con Entrada de Voltaje/química , Secuencia de Aminoácidos , Benzodiazepinas/farmacología , Sitios de Unión , Diseño de Fármacos , Humanos , Técnicas In Vitro , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Molecular , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Conformación Proteica , Homología de Secuencia de AminoácidoRESUMEN
A chemical feature based pharmacophore model was developed for alpha(1A)-adrenoceptor antagonists by HypoGen module implemented in catalyst software package. The best scoring pharmacophore hypothesis, Hypo1, consisted of four important chemical features (one positive ion, one hydrogen-bond donor, one aromatic ring, and one hydrophobic group). The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/química , Sistemas Especialistas , Modelos Moleculares , Antagonistas Adrenérgicos alfa/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Receptores Adrenérgicos alfa 1 , Programas Informáticos , Relación Estructura-ActividadRESUMEN
Predictive pharmacophore models were developed for a large series of I(Kr) potassium channel blockers as class III antiarrhythmic agents using HypoGen in Catalyst software. The pharmacophore hypotheses were generated using a training set consisting of 34 compounds carefully selected from documents. Their biological data, expressed as IC(50), spanned from 1.5 nM to 2.8 mM with 7 orders difference. The most predictive hypothesis (Hypo1), consisting of four features (one positive ionizable feature, two aromatic rings and one hydrophobic group), had a best correlation coefficient of 0.825, a lowest rms deviation of 1.612, and a highest cost difference (null cost-total cost) of 77.552, which represents a true correlation and a good predictivity. The hypothesis Hypo1 was then validated by a test set consisting of 21 compounds and by a cross-validation of 95% confidence level with randomizing the data using CatScramble program. Accordingly, our model has strong predictivity to identify structural diverse I(Kr) potassium channel blockers with desired biological activity by virtual screening