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1.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670795

RESUMEN

Adenia viridiflora Craib. is an indigenous edible plant that became an endangered species due to limited consumption of the local population with unknown reproduction and growth conditions. The plant is used as a traditional herb; however, its health applications lack scientific-based evidence. A. viridiflora Craib. plant parts (old leaves and young shoots) from four areas as Kamphaeng Phet (KP), Muang Nakhon Ratchasima (MN), Pakchong Nakhon Ratchasima (PN), and Uthai Thani (UT) origins were investigated for phenolic compositions and in vitro health properties through the inhibition of key enzymes relevant to obesity (lipase), diabetes (α-glucosidase and dipeptidyl peptidase-IV), Alzheimer's disease (cholinesterases and ß-secretase), and hypertension (angiotensin-converting enzyme). Phenolics including p-coumaric acid, sinapic acid, naringenin, and apigenin were detected in old leaves and young shoots in all plant origins. Old leaves exhibited higher total phenolic contents (TPCs) and total flavonoid contents (TFCs), leading to higher enzyme inhibitory activities than young shoots. Besides, PN and MN with higher TPCs and TFCs tended to exhibit greater enzyme inhibitory activities than others. These results will be useful to promote this plant as a healthy food with valuable medicinal capacities to support its consumption and agricultural stimulation, leading to sustainable conservation of this endangered species.


Asunto(s)
Enfermedad , Passifloraceae/química , Fitoterapia , Extractos Vegetales/química , Agua/química , Animales , Antioxidantes/análisis , Candida/enzimología , Cromatografía Líquida de Alta Presión , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Flavonoides/análisis , Caballos , Humanos , Hipertensión/tratamiento farmacológico , Fenoles/análisis , Hojas de la Planta/química , Brotes de la Planta/química , Conejos , Saccharomyces cerevisiae/enzimología , Solventes
2.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671811

RESUMEN

Marine algae are a promising source of potent bioactive agents against oxidative stress, diabetes, and inflammation. However, the possible therapeutic effects of many algal metabolites have not been exploited yet. In this regard, we explored the therapeutic potential of Enteromorpha intestinalis extracts obtained from methanol, ethanol, and hexane, in contrasting oxidative stress. The total phenolic (TPC) and flavonoids (TFC) content were quantified in all extracts, with ethanol yielding the best values (about 60 and 625 mg of gallic acid and rutin equivalents per gram of extract, respectively). Their antioxidant potential was also assessed through DPPH•, hydroxyl radical, hydrogen peroxide, and superoxide anion scavenging assays, showing a concentration-dependent activity which was greater in the extracts from protic and more polar solvents. The α-amylase and α-glucosidase activities were estimated for checking the antidiabetic capacity, with IC50 values of about 3.8 µg/mL for the methanolic extract, almost as low as those obtained with acarbose (about 2.8 and 3.3 µg/mL, respectively). The same extract also showed remarkable anti-inflammatory effect, as determined by hemolysis, protein denaturation, proteinase and lipoxygenase activity assays, with respectable IC50 values (about 11, 4, 6, and 5 µg/mL, respectively), also in comparison to commercially used drugs, such as acetylsalicylic acid.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Ulva/química , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Compuestos de Bifenilo/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Flavonoides/química , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Humanos , Radical Hidroxilo/antagonistas & inhibidores , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Lipooxigenasas/metabolismo , Masculino , Péptido Hidrolasas/metabolismo , Fenoles/química , Fenoles/aislamiento & purificación , Fenoles/farmacología , Picratos/antagonistas & inhibidores , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Superóxidos/antagonistas & inhibidores
3.
Food Chem ; 352: 129369, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33706137

RESUMEN

The development of tyrosinase inhibitors to prevent the enzymatic browning have become a research hotspot in food industry. 4-Hydroxycinnamic acid (CA) and ferulic acid (FA) are both the derivates of cinnamic acids, which are widely coexisted in plants seeds and leaves. CA combined with FA (inhibition rate of 90.44%) were found to effectively inhibit tyrosinase activity than employing CA and FA alone (inhibition rate of 12.15% and 22.17%, respectively). CA-FA-tyrosinase complex resulted in fluorescence quenching. The first-order kinetics and Weibull models well described the inactivation of tyrosinase at 2-4 mM and 6-10 mM of CA and FA, respectively. Additionally, UV-vis spectrum indicated that several characteristic groups such as hydroxyl group in CA competed with the nucleophilic attack of intramolecular cyclization, leading to the decrease of characteristic peak. Molecular docking further studied that CA and FA interacted with the activity cavity of tyrosinase by amino acids residues Ser282, His263, and Val283.


Asunto(s)
Ácidos Cumáricos/farmacología , Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Interacciones Farmacológicas , Cinética , Simulación del Acoplamiento Molecular
4.
Nat Commun ; 12(1): 1864, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767144

RESUMEN

Extracellular vesicles (EVs), including exosomes, are thought to mediate intercellular communication through the transfer of cargoes from donor to acceptor cells. Occurrence of EV-content delivery within acceptor cells has not been unambiguously demonstrated, let alone quantified, and remains debated. Here, we developed a cell-based assay in which EVs containing luciferase- or fluorescent-protein tagged cytosolic cargoes are loaded on unlabeled acceptor cells. Results from dose-responses, kinetics, and temperature-block experiments suggest that EV uptake is a low yield process (~1% spontaneous rate at 1 h). Further characterization of this limited EV uptake, through fractionation of membranes and cytosol, revealed cytosolic release (~30% of the uptaken EVs) in acceptor cells. This release is inhibited by bafilomycin A1 and overexpression of IFITM proteins, which prevent virus entry and fusion. Our results show that EV content release requires endosomal acidification and suggest the involvement of membrane fusion.


Asunto(s)
Antígenos de Diferenciación/metabolismo , Transporte Biológico/fisiología , Comunicación Celular/fisiología , Vesículas Extracelulares/metabolismo , Línea Celular Tumoral , Citosol/metabolismo , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes/metabolismo , Células HEK293 , Células HeLa , Humanos , Luciferasas/metabolismo , Macrólidos/farmacología , Fusión de Membrana/fisiología
5.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668468

RESUMEN

Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/enzimología , Nicotinamida N-Metiltransferasa/antagonistas & inhibidores , Animales , Sitios de Unión , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Ligandos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Niacinamida/metabolismo , Nicotinamida N-Metiltransferasa/metabolismo , Ratas , Especificidad por Sustrato/efectos de los fármacos
6.
Food Chem ; 351: 129338, 2021 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-33647700

RESUMEN

Hyperstable cysteine-rich peptides (CRPs) represent an underexplored superfamily of bioactives in functional foods. An example is wolfberry of the Lycium barbarum family. Previously, we discovered a CRP, designated α-lybatide, from L. barbarum bark. Herein, we report the discovery of ß-lybatide, a novel carboxypeptidase inhibitor belonging to a different CRP family from the wolfberry plant. Proteomic and transcriptomic analyses showed that ß-lybatide contains 36 amino acids with six cysteine residues. NMR spectroscopy revealed that ß-lybatide displays a knottin-like structure that renders it highly resistant to thermal, chemical and enzymatic degradation, conditions important for keeping its structural integrity in gastrointestinal tract. Biochemical assays showed that ß-lybatide is a potent carboxypeptidase inhibitor which could contribute to the wolfberry biological activities. Bioinformatics analysis revealed an additional 49 ß-lybatide-like plant carboxypeptidase inhibitors. Together, our results show that ß-lybatide is the first and the smallest plant-derived hyperstable carboxypeptidase inhibitor discovered from a functional food.


Asunto(s)
Carboxipeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Lycium/química , Péptidos/farmacología , Cisteína , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Lycium/metabolismo , Péptidos/química , Péptidos/metabolismo , Proteómica
7.
Nat Commun ; 12(1): 1782, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741963

RESUMEN

Pharmacological inhibition of vacuolar-type H+-ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a, thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7'-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c.


Asunto(s)
Macrólidos/farmacología , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Sitios de Unión , Biocatálisis/efectos de los fármacos , Bovinos , Microscopía por Crioelectrón , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Macrólidos/química , Macrólidos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Dominios Proteicos , Homología de Secuencia de Aminoácido , ATPasas de Translocación de Protón Vacuolares/química , ATPasas de Translocación de Protón Vacuolares/ultraestructura
8.
Nat Commun ; 12(1): 1946, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782401

RESUMEN

Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Ribonucleoproteína Nuclear Heterogénea A1/genética , Neoplasias de la Próstata/genética , Proteína-Arginina N-Metiltransferasas/genética , Empalme Alternativo , Secuencia de Aminoácidos , Arginina/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Inhibidores Enzimáticos/farmacología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Ribonucleoproteína Nuclear Heterogénea A1/antagonistas & inhibidores , Ribonucleoproteína Nuclear Heterogénea A1/metabolismo , Humanos , Masculino , Metilación/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Empalmosomas/efectos de los fármacos , Empalmosomas/genética , Empalmosomas/metabolismo , Especificidad por Sustrato
9.
Nat Struct Mol Biol ; 28(3): 319-325, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33674802

RESUMEN

The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.


Asunto(s)
Antivirales/farmacología , /química , Inhibidores Enzimáticos/farmacología , Suramina/farmacología , Animales , Antivirales/química , Antivirales/metabolismo , Sitios de Unión , Dominio Catalítico , Chlorocebus aethiops , Microscopía por Crioelectrón , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Conformación Proteica , ARN Viral/química , ARN Viral/metabolismo , Suramina/química , Suramina/metabolismo , Células Vero , Replicación Viral/efectos de los fármacos
10.
Eur J Pharmacol ; 896: 173922, 2021 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-33539819

RESUMEN

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.


Asunto(s)
/antagonistas & inhibidores , Doxorrubicina/análogos & derivados , Lopinavir/farmacología , Serina Endopeptidasas/metabolismo , Internalización del Virus/efectos de los fármacos , Antivirales/farmacología , /metabolismo , Doxorrubicina/farmacología , Reposicionamiento de Medicamentos , Inhibidores Enzimáticos/clasificación , Inhibidores Enzimáticos/farmacología , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , /fisiología , Inhibidores de Topoisomerasa II/farmacología
11.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589584

RESUMEN

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Mieloma Múltiple/tratamiento farmacológico , Coactivador 3 de Receptor Nuclear/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Resistencia a Antineoplásicos/genética , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Coactivador 3 de Receptor Nuclear/antagonistas & inhibidores , Coactivador 3 de Receptor Nuclear/metabolismo , Inhibidores de Proteasoma/farmacología , Recurrencia , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Commun Biol ; 4(1): 193, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33564093

RESUMEN

SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site. Our findings provide new insights for the development of uracil scaffold-based drugs.


Asunto(s)
Antivirales/farmacología , /virología , Endorribonucleasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Pirrolidinas/farmacología , /enzimología , Timina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Células A549 , Antivirales/química , Antivirales/farmacocinética , Dominio Catalítico , Cristalografía por Rayos X , Endorribonucleasas/química , Endorribonucleasas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ligandos , Modelos Moleculares , Conformación Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Timina/química , Timina/farmacocinética , Uridina/metabolismo , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo
13.
Phytochemistry ; 184: 112664, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524855

RESUMEN

From solid rice-based cultures of Malbranchea albolutea, three undescribed ardeemins and sartoryglabrins analogs were discovered and named alboluteins A-C. 1H-Indole-3-carbaldehyde, and anthranilic acid were also isolated. 1D and 2D-NMR techniques, as well as DFT-calculated chemical shifts, allowed characterizing alboluteins A-C. Testing these compounds against PTP1B indicated their inhibitory activity with IC50's ranging from 19 to 129 µM (ursolic acid IC50 = 29.8 µM, positive control). Kinetic analysis revealed that albolutein C behaved as a non-competitive inhibitor. Docking studies of alboluteins A-C into the crystal structure of PTP1B (PDB ID: 1T49) predicted that all compounds prefer to bind at the allosteric site of the enzyme, with Ki values of 2.02 × 10-4, 1.31 × 10-4, and 2.67 × 10-4 mM, respectively. Molecular dynamic studies indicated that the active compounds remained tied to the enzyme with good binding energy.


Asunto(s)
Inhibidores Enzimáticos , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Inhibidores Enzimáticos/farmacología , Hongos/metabolismo , Cinética , Simulación del Acoplamiento Molecular , Onygenales , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo
14.
Int J Nanomedicine ; 16: 1143-1155, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603373

RESUMEN

Nanozyme is a type of nanomaterial with intrinsic enzyme-like activity. Following the discovery of nanozymes in 2007, nanozyme technology has become an emerging field bridging nanotechnology and biology, attracting research from multi-disciplinary areas focused on the design and synthesis of catalytically active nanozymes. However, various types of enzymes can be mimicked by nanomaterials, and our current understanding of nanozymes as enzyme inhibitors is limited. Here, we provide a brief overview of the utility of nanozymes as inhibitors of enzymes, such as R-chymotrypsin (ChT), ß-galactosidase (ß-Gal), ß-lactamase, and mitochondrial F0F1-ATPase, and the mechanisms underlying inhibitory activity. The advantages, challenges and future research directions of nanozymes as enzyme inhibitors for biomedical research are further discussed.


Asunto(s)
Biomimética , Inhibidores Enzimáticos/farmacología , Enzimas/química , Nanoestructuras/química , Animales , Catálisis , Humanos , Nanotecnología
15.
Can J Physiol Pharmacol ; 99(3): 284-293, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33635146

RESUMEN

The Wnt/ß-catenin pathway, which interferes with cell proliferation, differentiation, and autophagy, is commonly dysregulated in colorectal cancer (CRC). Mutation of the RAS oncogene is the most prevalent genetic alteration in CRC and has been linked to activation of protein kinase B (AKT) signaling. Phosphorylation of ß-catenin at Ser 552 by AKT contributes to ß-catenin stability, transcriptional activity, and increase of cell proliferation. Casein kinase 1 alpha (CK1α) is an enzyme that simultaneously regulates Wnt/ß-catenin and AKT. The link of the AKT and Wnt pathway to autophagy in RAS-mutated CRC cells has not well identified. Therefore, we investigated how pharmacological CK1α inhibition (D4476) is involved in regulation of autophagy, Wnt/ß-catenin, and AKT pathways in RAS-mutated CRC cell lines. qRT-PCR and immunoblotting experiments revealed that phospho-AKT (S473) and phospho-ß-catenin (S552) are constitutively increased in RAS-mutated CRC cell lines, in parallel with augmented CK1α expression. The results also showed that D4476 significantly reduced the AKT/phospho-ß-catenin (S552) axis concomitantly with autophagy flux inhibition in RAS-mutated CRC cells. Furthermore, D4476 significantly induced apoptosis in RAS-mutated CRC cells. In conclusion, our results indicate that CK1α inhibition reduces autophagy flux and promotes apoptosis by interfering with the AKT/phospho-ß-catenin (S552) axis in RAS-mutated CRC cells.


Asunto(s)
Autofagia/efectos de los fármacos , Neoplasias Colorrectales/genética , Genes ras/genética , Proteína Oncogénica v-akt/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , beta Catenina/efectos de los fármacos , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células HCT116 , Humanos , Mutación , Fosforilación , beta Catenina/antagonistas & inhibidores
16.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33526596

RESUMEN

The RNA polymerase inhibitor favipiravir is currently in clinical trials as a treatment for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, nonproductive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp, which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.


Asunto(s)
Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirazinas/farmacología , /ultraestructura , Amidas/química , /química , Microscopía por Crioelectrón/métodos , Inhibidores Enzimáticos/química , Pirazinas/química , Ribonucleótidos/química , /enzimología , Imagen Individual de Molécula/métodos
17.
J Med Chem ; 64(3): 1701-1712, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33529017

RESUMEN

Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Animales , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Fase G2/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-Dawley , Solubilidad , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Biomed Pharmacother ; 137: 111313, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33556871

RESUMEN

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CLpro), papain-like protease (PLpro) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.


Asunto(s)
Antivirales , Terapia Molecular Dirigida/métodos , Antivirales/clasificación , Antivirales/farmacología , /metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , /enzimología , Terapias en Investigación
19.
Nat Commun ; 12(1): 421, 2021 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-33462210

RESUMEN

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.


Asunto(s)
Antineoplásicos/farmacología , Enfermedades Óseas/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/uso terapéutico , Enfermedades Óseas/diagnóstico , Enfermedades Óseas/genética , Enfermedades Óseas/patología , Médula Ósea/patología , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , Femenino , Fémur/diagnóstico por imagen , Fémur/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Ensayos Antitumor por Modelo de Xenoinjerto
20.
J Enzyme Inhib Med Chem ; 36(1): 497-503, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33491508

RESUMEN

COVID-19 has become a global pandemic and there is an urgent call for developing drugs against the virus (SARS-CoV-2). The 3C-like protease (3CLpro) of SARS-CoV-2 is a preferred target for broad spectrum anti-coronavirus drug discovery. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredients. We found that the ethanol extract of S. baicalensis and its major component, baicalein, inhibit SARS-CoV-2 3CLpro activity in vitro with IC50's of 8.52 µg/ml and 0.39 µM, respectively. Both of them inhibit the replication of SARS-CoV-2 in Vero cells with EC50's of 0.74 µg/ml and 2.9 µM, respectively. While baicalein is mainly active at the viral post-entry stage, the ethanol extract also inhibits viral entry. We further identified four baicalein analogues from other herbs that inhibit SARS-CoV-2 3CLpro activity at µM concentration. All the active compounds and the S. baicalensis extract also inhibit the SARS-CoV 3CLpro, demonstrating their potential as broad-spectrum anti-coronavirus drugs.


Asunto(s)
Antivirales/farmacología , /antagonistas & inhibidores , Flavanonas/farmacología , Extractos Vegetales/farmacología , Inhibidores de Proteasas/farmacología , Replicación Viral/efectos de los fármacos , Animales , /virología , Chlorocebus aethiops , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Modelos Moleculares , Células Vero
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