Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 178.904
Filtrar
1.
Pestic Biochem Physiol ; 172: 104749, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33518042

RESUMEN

Plant viral diseases, known as "plant cancer", with high contagiosity can substantially reduce crop quality and yield. To identify potential anti-tobacco mosaic virus (TMV) agents with different mechanisms, a series of novel α-aminophosphonate derivatives containing a chalcone moiety were designed and synthesized. Bioassay results revealed that some target compounds exhibited improved curative activity against TMV in vivo, and the EC50 value of compound B3 was 356.7 mg L-1. The activities of the defensive enzymes POD and CAT from tobacco leaves treated with B3 and B17 showed that these target compounds could improve the photosynthetic ability of the leaves and activate plant host resistance against TMV infection. The binding constant between B3 and TMV Coat Protein (CP) (2.51 × 108 M-1), calculated by the fluorescence titration experiment and docking results, revealed that B3 has a strong interaction with TMV CP. Further docking analysis revealed that B3 was embedded between two layers of the TMV CP, which was consistent with the 2:1 binding mode of TMV CP and B3 determined by the binding affinity experiment. The TEM morphological study of TMV treated with B3 and B17 indicated that this series of target compounds may trigger the disassembly of TMV by interacting directly with TMV CP. This study provides new insight for the discovery of antiviral compounds with two different mechanisms of action.


Asunto(s)
Antivirales , Chalcona , Chalconas , Virus del Mosaico del Tabaco , Antivirales/farmacología , Chalconas/farmacología , Enfermedades de las Plantas , Relación Estructura-Actividad , Tabaco
2.
Pestic Biochem Physiol ; 172: 104766, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33518053

RESUMEN

According to the pharmacophore binding strategy and principle of bioelectronic isobaric, used the sulfonylurea bridge as the parent structure, a series of novel thiourea compounds containing aromatic-substituted pyrimidines were designed and synthesized. The preliminary herbicidal activity tests showed that some compounds had good herbicidal activity against Digitaria adscendens, Amaranthus retroflexus, especially for compound 4d and 4f. The results showed that compound 4d had an inhibition rate of 81.5% on the root growth of Brassica napus L. at the concentration of 100 mg L-1, and compound 4f had an inhibition rate of 81% on the root growth of Digitaria adscendens at the concentration of 100 mg L-1. Compounds 4d and 4f had higher comparative activity on Echinochloa crus-galli than the commercial herbicide bensulfuron-methyl. The preliminary structure-activity relationship (SAR) was also summarized. We also tested the in vivo AHAS enzyme activity inhibition experiment of 14 compounds at 100 mg L-1, and the results showed that they all have inhibitory activity on the enzyme, with the highest inhibition rate reaching 44.4% (compound 4d). Based on the results of molecular docking to yeast acetohydroxyacid synthase (AHAS), the possible herbicidal activity mechanism of these compounds was evaluated.


Asunto(s)
Acetolactato Sintasa , Herbicidas , Acetolactato Sintasa/metabolismo , Herbicidas/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiourea/farmacología
3.
Nat Commun ; 12(1): 1052, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594070

RESUMEN

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates. We describe the development of novel small molecule allosteric inhibitors of trypanosome phosphofructokinase (PFK) that block the glycolytic pathway resulting in very fast parasite kill times with no inhibition of human PFKs. The compounds cross the blood brain barrier and single day oral dosing cures parasitaemia in a stage 1 animal model of human African trypanosomiasis. This study demonstrates that it is possible to target glycolysis and additionally shows how differences in allosteric mechanisms may allow the development of species-specific inhibitors to tackle a range of proliferative or infectious diseases.


Asunto(s)
Glucólisis/efectos de los fármacos , Fosfofructoquinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Trypanosoma/enzimología , Tripanosomiasis Africana/metabolismo , Tripanosomiasis Africana/parasitología , Enfermedad Aguda , Regulación Alostérica/efectos de los fármacos , Animales , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Ratones , Parásitos/efectos de los fármacos , Fosfofructoquinasas/química , Fosfofructoquinasas/metabolismo , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína , Relación Estructura-Actividad , Trypanosoma/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico
4.
Nat Commun ; 12(1): 297, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436612

RESUMEN

GABAA receptors (GABAARs) are the primary fast inhibitory ion channels in the central nervous system. Dysfunction of trafficking and localization of GABAARs to cell membranes is clinically associated with severe psychiatric disorders in humans. The GABARAP protein is known to support the stability of GABAARs in synapses, but the underlying molecular mechanisms remain to be elucidated. Here, we show that GABARAP/GABARAPL1 directly binds to a previously unappreciated region in the γ2 subunit of GABAAR. We demonstrate that GABARAP functions to stabilize GABAARs via promoting its trafficking pathway instead of blocking receptor endocytosis. The GABARAPL1-γ2-GABAAR crystal structure reveals the mechanisms underlying the complex formation. We provide evidence showing that phosphorylation of γ2-GABAAR differentially modulate the receptor's binding to GABARAP and the clathrin adaptor protein AP2. Finally, we demonstrate that GABAergic synaptic currents are reduced upon specific blockage of the GABARAP-GABAAR complex formation. Collectively, our results reveal that GABARAP/GABARAPL1, but not other members of the Atg8 family proteins, specifically regulates synaptic localization of GABAARs via modulating the trafficking of the receptor.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Neuronas GABAérgicas/metabolismo , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Receptores de GABA-A/metabolismo , Transmisión Sináptica , Complejo 2 de Proteína Adaptadora/química , Complejo 2 de Proteína Adaptadora/metabolismo , Secuencias de Aminoácidos , Animales , Familia de las Proteínas 8 Relacionadas con la Autofagia , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Fosforilación , Unión Proteica , Estructura Secundaria de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/metabolismo , Transporte de Proteínas , Células Piramidales/metabolismo , Ratas , Receptores de GABA-A/química , Relación Estructura-Actividad
5.
Nat Commun ; 12(1): 28, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397924

RESUMEN

SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface.


Asunto(s)
Núcleo Celular/metabolismo , Factores de Transcripción SOXB1/química , Factores de Transcripción SOXB1/metabolismo , Transporte Activo de Núcleo Celular , Secuencia de Aminoácidos , Animales , Drosophila/metabolismo , Células HEK293 , Humanos , Ratones , Modelos Moleculares , Proteínas Mutantes/metabolismo , Células-Madre Neurales/metabolismo , Señales de Localización Nuclear/metabolismo , Mutación Puntual/genética , Unión Proteica , Dominios Proteicos , Isoformas de Proteínas/metabolismo , Factores de Transcripción SOXB1/genética , Relación Estructura-Actividad
6.
Nat Commun ; 12(1): 44, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33398001

RESUMEN

In Bacteroidetes, one of the dominant phyla of the mammalian gut, active uptake of large nutrients across the outer membrane is mediated by SusCD protein complexes via a "pedal bin" transport mechanism. However, many features of SusCD function in glycan uptake remain unclear, including ligand binding, the role of the SusD lid and the size limit for substrate transport. Here we characterise the ß2,6 fructo-oligosaccharide (FOS) importing SusCD from Bacteroides thetaiotaomicron (Bt1762-Bt1763) to shed light on SusCD function. Co-crystal structures reveal residues involved in glycan recognition and suggest that the large binding cavity can accommodate several substrate molecules, each up to ~2.5 kDa in size, a finding supported by native mass spectrometry and isothermal titration calorimetry. Mutational studies in vivo provide functional insights into the key structural features of the SusCD apparatus and cryo-EM of the intact dimeric SusCD complex reveals several distinct states of the transporter, directly visualising the dynamics of the pedal bin transport mechanism.


Asunto(s)
Proteínas Bacterianas/metabolismo , Microbioma Gastrointestinal , Polisacáridos/metabolismo , Simbiosis , Proteínas Bacterianas/química , Microscopía por Crioelectrón , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Oligosacáridos/química , Polisacáridos/química , Conformación Proteica , Relación Estructura-Actividad
7.
Nat Commun ; 12(1): 46, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397902

RESUMEN

The exploration of highly efficient processes to convert renewable biomass to fuels and value-added chemicals is stimulated by the energy and environment problems. Herein, we describe an innovative route for the production of methylcyclopentadiene (MCPD) with cellulose, involving the transformation of cellulose into 3-methylcyclopent-2-enone (MCP) and subsequent selective hydrodeoxygenation to MCPD over a zinc-molybdenum oxide catalyst. The excellent performance of the zinc-molybdenum oxide catalyst is attributed to the formation of ZnMoO3 species during the reduction of ZnMoO4. Experiments reveal that preferential interaction of ZnMoO3 sites with the C=O bond instead of C=C bond in vapor-phase hydrodeoxygenation of MCP leads to highly selective formations of MCPD (with a carbon yield of 70%).


Asunto(s)
Celulosa/química , Ciclopentanos/química , Óxidos/química , Oxígeno/química , Adsorción , Catálisis , Relación Estructura-Actividad , Difracción de Rayos X
8.
J Med Chem ; 64(2): 1170-1179, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33426889

RESUMEN

Ifenprodil (1) is a potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over α, σ, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (Ki = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ1 receptors.


Asunto(s)
Antifibrinolíticos/química , Antifibrinolíticos/farmacología , Antivirales/química , Antivirales/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Antifibrinolíticos/síntesis química , Antivirales/síntesis química , /metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
9.
Molecules ; 26(2)2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-33435264

RESUMEN

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Diabetes Mellitus/tratamiento farmacológico , Inhibidores Enzimáticos , Hipoglucemiantes , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Aldehído Reductasa/metabolismo , Animales , Diabetes Mellitus/enzimología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células Hep G2 , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ligandos , Ratones , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Relación Estructura-Actividad
10.
Nat Commun ; 12(1): 449, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33469028

RESUMEN

Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.


Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/ultraestructura , Proteínas Bacterianas/ultraestructura , Esteroides/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/química , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa/farmacología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Sitios de Unión , Coenzimas/química , Coenzimas/metabolismo , Coenzimas/ultraestructura , Cristalografía por Rayos X , Diseño de Fármacos , Enlace de Hidrógeno , NADP/química , NADP/metabolismo , NADP/ultraestructura , Oxidación-Reducción , Proteobacteria/enzimología , Relación Estructura-Actividad
11.
Sci Total Environ ; 765: 144427, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33418328

RESUMEN

A series of actinia-shaped lignin-based adsorbents (LNAEs) featuring lignin (LN) as the core and grafted poly(acrylic acid) (PAA) as the tentacle were designed and fabricated. Two fluoroquinolones (FQs) with similar molecular structures, ofloxacin (OFL) and ciprofloxacin (CIP), were used as targets to study the selective adsorption performance of LNAEs associated with the structural effects of the LN-based adsorbents in FQs binary aqueous system. The adsorption of the two FQs by LNAEs complied with the competitive Langmuir isothermal model, and showed selective removal of CIP over OFL due to the additional negative charge-assisted hydrogen bond (CAHB) formed between the carboxyl group of LNAEs and the secondary amino group of CIP, in addition to the effects of electrostatic attraction and normal hydrogen bonds, according to quantitative studies and density functional theory analysis. A binary nonlinear model based on phenomenological theory was applied to study the effects of PAA branched-chain length and distribution on the selective adsorption performance of the LN-based adsorbents. Accordingly, the branched-chain distribution played a more important role and higher distribution density of branched PAA could expose more adsorption sites on LNAEs' surface and improve the adsorptive selectivity. This study offers a well understanding of the structure-activity relationship of the surface grafting-modified adsorbents in binary pollutant systems and fundamental guidance for the exploitation and design of novel and efficient adsorbents.


Asunto(s)
Ciprofloxacino , Contaminantes Químicos del Agua , Adsorción , Cinética , Lignina , Ofloxacino/análisis , Relación Estructura-Actividad , Contaminantes Químicos del Agua/análisis
12.
Yakugaku Zasshi ; 141(1): 15-24, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390442

RESUMEN

Iminosugars are one of the compounds that mimic the structure of monosaccharides. Such sugar mimics have the ability to effectively and specifically inhibit various glycosidases and glycosyltransferases. After studying iminopyranose, miglitol, which has α-glucosidase inhibitory activity, was approved and used in the clinical treatment of diabetes. This study focused on l-iminofuranose derivatives to develop new anti-diabetic drug. As a result, it was found that l-iminofuranose having an alkyl group at C1 position show potent α-glucosidase inhibitory activity. Further structural-activity relationship studies were conducted, and interesting findings were obtained. This paper describes the details of those research developments.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Diabetes Mellitus/tratamiento farmacológico , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Iminopiranosas/síntesis química , Iminopiranosas/farmacología , 1-Desoxinojirimicina/síntesis química , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Animales , Humanos , Iminopiranosas/química , Iminopiranosas/uso terapéutico , Relación Estructura-Actividad , alfa-Glucosidasas
13.
Yakugaku Zasshi ; 141(1): 41-45, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-33390446

RESUMEN

Diabetic retinopathy (DR) is a retinal disease representing one of the main causes of vision loss in developed countries. In the early stage of DR, disruption of blood retinal barrier (BRB) is observed, and it will lead to vascular permeability and visual impairment. Therefore, protection against the breakdown of BRB may be useful strategy for prevention of DR. Matrix metalloproteinases (MMPs) plays an important role in the degradation of extracellular matrix proteins. In DR, they attribute to increased vascular permeability by degrading the junction proteins, such as occuldin and cadherin that are important to maintain the BRB junction complex. Müller cells constitute the main glial cells of the retina and are involved in many retinal functions. They are reported to be one of the MMP-producing cells in the retina. In this symposium review, I present the molecular mechanism of MMP expression in retinal Müller cells. In addition, I would like to introduce polymethoxylated flavones, nobiletin and the derivatives isolated from natural resource as novel MMP inhibitors, which may be applicable to prevention of DR.


Asunto(s)
Retinopatía Diabética/etiología , Retinopatía Diabética/prevención & control , Células Ependimogliales/enzimología , Flavonas/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Fitoterapia , Animales , Barrera Hematorretinal/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Flavonas/aislamiento & purificación , Flavonas/uso terapéutico , Humanos , Ratones , Relación Estructura-Actividad
14.
J Med Chem ; 64(1): 719-740, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33395287

RESUMEN

Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.


Asunto(s)
Antituberculosos/química , Pirimidinonas/química , Animales , Antituberculosos/metabolismo , Antituberculosos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Semivida , Humanos , Hierro/metabolismo , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Microsomas/metabolismo , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Pirazoles/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacología , Ratas , Relación Estructura-Actividad
15.
J Med Chem ; 64(1): 845-860, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33399453

RESUMEN

Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.


Asunto(s)
5'-Nucleotidasa/antagonistas & inhibidores , Ácidos Fosforosos/química , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Simulación de Dinámica Molecular , Ácidos Fosforosos/metabolismo , Relación Estructura-Actividad
16.
J Med Chem ; 64(1): 741-767, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33400524

RESUMEN

Erlotinib was covalently linked to 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) and structurally related chlorins and bacteriochlorins at different positions of the tetrapyrrole ring. The functional consequence of each modification was determined by quantifying the uptake and subcellular deposition of the erlotinib conjugates, cellular response to therapeutic light treatment in tissue cultures, and in eliminating of corresponding tumors grown as a xenograft in SCID mice. The experimental human cancer models the established cell lines UMUC3 (bladder), FaDu (hypopharynx), and primary cultures of head and neck tumor cells. The effectiveness of the compounds was compared to that of HPPH. Furthermore, specific functional contribution of the carboxylic acid side group at position 172 and the chiral methyl group at 3(1') to the overall activity of the chimeric compounds was assessed. Among the conjugates investigated, the PS 10 was identified as the most effective candidate for achieving tumor cell-specific accumulation and yielding improved long-term tumor control.


Asunto(s)
Clorhidrato de Erlotinib/química , Fármacos Fotosensibilizantes/síntesis química , Porfirinas/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Ratones , Ratones SCID , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad , Tasa de Supervivencia
17.
J Med Chem ; 64(1): 768-781, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33440945

RESUMEN

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1ß release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.


Asunto(s)
Antiinflamatorios/química , Berberina/química , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Berberina/metabolismo , Berberina/farmacología , Sitios de Unión , Humanos , Enlace de Hidrógeno , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Quinasas Relacionadas con NIMA/genética , Proteína con Dominio Pirina 3 de la Familia NLR/química , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad
18.
Life Sci ; 269: 119028, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33444618

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common cancer-related death in the world. No effective curative option exists for the treatment of HCC. The available drugs exhibit severe toxic effects and low therapeutic index. AIM: This work aimed to examine different monocationic arylthiophene derivatives for possible use as chemotherapeutic agents against HCC. METHODS: The IC50 values for the compounds were determined. The mechanism of cytotoxicity was further investigated using different methods. RESULTS: Compound 2j proved to retain the highest cytotoxicity in comparison to as a positive control. The selectivity index of compound 2j revealed the safety to normal cells. Moreover, compound 2j was able to inhibit HepG2 cells´ migration and division. The anticancer effect of compound 2j was found to be partially via cell cycle arrest, activation of the tumour suppressor p53 protein, and induction of apoptosis via both intrinsic and extrinsic pathways. Compound 2j has a potential sensitization activity and significantly reduced the IC50 values for the anticancer drugs doxorubicin, cisplatin, and taxol. CONCLUSION: The tested arylthiophenes showed a potent cytotoxicity against HepG2 cells and were safe to normal cells. The most active compound 2j was found to be able to inhibit cell division and migration and also to induce apoptosis. Compound 2j also proved to have a sensitization effect on standard anticancer drugs.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Tiofenos/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Carcinoma Hepatocelular/patología , Caspasas/metabolismo , Cationes , Puntos de Control del Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Doxorrubicina/farmacología , Activación Enzimática/efectos de los fármacos , Fase G2/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Mitosis/efectos de los fármacos , Paclitaxel/farmacología , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Ensayo de Tumor de Célula Madre , Cicatrización de Heridas/efectos de los fármacos
19.
Phys Rev Lett ; 126(2): 028102, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33512186

RESUMEN

The ability to reroute and control flow is vital to the function of venation networks across a wide range of organisms. By modifying individual edges in these networks, either by adjusting edge conductances or creating and destroying edges, organisms robustly control the propagation of inputs to perform specific tasks. However, a fundamental disconnect exists between the structure and function: networks with different local architectures can perform the same functions. Here, we answer the question of how changes at the level of individual edges collectively create functionality at the scale of an entire network. Using persistent homology, we analyze networks tuned to perform complex tasks. We find that the responses of such networks encode a hidden topological structure composed of sectors of nearly uniform pressure. Although these sectors are not apparent in the underlying network structure, they correlate strongly with the tuned function. The connectivity of these sectors, rather than that of individual nodes, provides a quantitative relationship between structure and function in flow networks.


Asunto(s)
Microvasos , Modelos Biológicos , Animales , Relación Estructura-Actividad
20.
Nat Commun ; 12(1): 602, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504803

RESUMEN

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1 Å and 2.4 Å resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Proteínas Bacterianas/inmunología , Proteínas de Transporte de Membrana/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Tuberculosis/prevención & control , Adulto , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Linfocitos B/inmunología , Proteínas Bacterianas/química , Epítopos/química , Humanos , Memoria Inmunológica , Masculino , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Secundaria de Proteína , Relación Estructura-Actividad , Células THP-1 , Tuberculosis/sangre , Tuberculosis/microbiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA