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1.
Chem Sci ; 14(26): 7136-7146, 2023 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-37416723

RESUMEN

Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited. Here we report a potent and selective de novo cyclic peptide inhibitor (OC9) targeting the Nε-trimethyllysine-binding PHD-fingers of the KDM7 histone demethylases, developed using mRNA display. OC9 disrupts PHD-finger interaction with histone H3K4me3 by engaging the Nε-methyllysine-binding aromatic cage through a valine, revealing a new non-lysine recognition motif for the PHD-fingers that does not require cation-π interaction. PHD-finger inhibition by OC9 impacted JmjC-domain mediated demethylase activity at H3K9me2, leading to inhibition of KDM7B (PHF8) but stimulation of KDM7A (KIAA1718), representing a new approach for selective allosteric modulation of demethylase activity. Chemoproteomic analysis showed selective engagement of OC9 with KDM7s in T cell lymphoblastic lymphoma SUP T1 cells. Our results highlight the utility of mRNA-display derived cyclic peptides for targeting challenging epigenetic reader proteins to probe their biology, and the broader potential of this approach for targeting protein-protein interactions.

2.
J Biol Chem ; 299(2): 102873, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36621625

RESUMEN

Variants of isocitrate dehydrogenase (IDH) 1 and 2 (IDH1/2) alter metabolism in cancer cells by catalyzing the NADPH-dependent reduction of 2-oxoglutarate (2OG) to (2R)-hydroxyglutarate. However, it is unclear how derivatives of 2OG can affect cancer cell metabolism. Here, we used synthetic C3- and C4-alkylated 2OG derivatives to investigate the substrate selectivities of the most common cancer-associated IDH1 variant (R132H IDH1), of two cancer-associated IDH2 variants (R172K IDH2, R140Q IDH2), and of WT IDH1/2. Absorbance-based, NMR, and electrochemical assays were employed to monitor WT IDH1/2 and IDH1/2 variant-catalyzed 2OG derivative turnover in the presence and absence of 2OG. Our results reveal that 2OG derivatives can serve as substrates of the investigated IDH1/2 variants, but not of WT IDH1/2, and have the potential to act as 2OG-competitive inhibitors. Kinetic parameters reveal that some 2OG derivatives, including the natural product 3-methyl-2OG, are equally or even more efficient IDH1/2 variant substrates than 2OG. Furthermore, NMR and mass spectrometry studies confirmed IDH1/2 variant-catalyzed production of alcohols in the cases of the 3-methyl-, 3-butyl-, and 3-benzyl-substituted 2OG derivatives; a crystal structure of 3-butyl-2OG with an IDH1 variant (R132C/S280F IDH1) reveals active site binding. The combined results highlight the potential for (i) IDH1/2 variant-catalyzed reduction of 2-oxoacids other than 2OG in cells, (ii) modulation of IDH1/2 variant activity by 2-oxoacid natural products, including some present in common foods, (iii) inhibition of IDH1/2 variants via active site binding rather than the established allosteric mode of inhibition, and (iv) possible use of IDH1/2 variants as biocatalysts.


Asunto(s)
Isocitrato Deshidrogenasa , Ácidos Cetoglutáricos , Humanos , Isocitrato Deshidrogenasa/química , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Ácidos Cetoglutáricos/química , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/farmacología , Neoplasias/metabolismo , Especificidad por Sustrato , Unión Proteica/efectos de los fármacos , Cristalografía
3.
Nat Commun ; 13(1): 4785, 2022 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-35970853

RESUMEN

Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged. We describe biochemical, crystallographic, and cellular studies on the IDH1 R132C/S280F and R132H/S280F variants that inform on the mechanism of second-site resistance, which involves both modulation of inhibitor binding at the IDH1 dimer-interface and alteration of kinetic properties, which enable more efficient 2-HG production relative to IDH1 R132C and IDH1 R132H. Importantly, the biochemical and cellular results demonstrate that it should be possible to overcome S280F mediated resistance in AML patients by using alternative inhibitors, including some presently in phase 2 clinical trials.


Asunto(s)
Resistencia a Antineoplásicos , Isocitrato Deshidrogenasa , Leucemia Mieloide Aguda , Resistencia a Antineoplásicos/genética , Glicina/análogos & derivados , Glicina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Piridinas/uso terapéutico
4.
Alzheimers Dement ; 18(12): 2637-2668, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35852137

RESUMEN

Hypoxia, that is, an inadequate oxygen supply, is linked to neurodegeneration and patients with cardiovascular disease are prone to Alzheimer's disease (AD). 2-Oxoglutarate and ferrous iron-dependent oxygenases (2OGDD) play a key role in the regulation of oxygen homeostasis by acting as hypoxia sensors. 2OGDD also have roles in collagen biosynthesis, lipid metabolism, nucleic acid repair, and the regulation of transcription and translation. Many biological processes in which the >60 human 2OGDD are involved are altered in AD patient brains, raising the question as to whether 2OGDD are involved in the transition from normal aging to AD. Here we give an overview of human 2OGDD and critically discuss their potential roles in AD, highlighting possible relationships with synapse dysfunction/loss. 2OGDD may regulate neuronal/glial differentiation through enzyme activity-dependent mechanisms and modulation of their activity has potential to protect against synapse loss. Work linking 2OGDD and AD is at an early stage, especially from a therapeutic perspective; we suggest integrated pathology and in vitro discovery research to explore their roles in AD is merited. We hope to help enable long-term research on the roles of 2OGDD and, more generally, oxygen/hypoxia in AD. We also suggest shorter term empirically guided clinical studies concerning the exploration of 2OGDD/oxygen modulators to help maintain synaptic viability are of interest for AD treatment.


Asunto(s)
Enfermedad de Alzheimer , Oxigenasas , Humanos , Oxigenasas/metabolismo , Ácidos Cetoglutáricos/metabolismo , Enfermedad de Alzheimer/metabolismo , Oxígeno , Hipoxia
5.
Regul Toxicol Pharmacol ; 132: 105192, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35654311

RESUMEN

The present study deals with the assessment of acrylamide levels, dietary intake and toxicity associated with food products which constitute the main components of a Lebanese breakfast including bread, crackers, toast and kaak. Quantification of acrylamide levels was performed on a UPLC-MS/MS spectrometer and upon correlation with the results of a community survey, the carcinogenic and neurotoxic risks associated with the dietary intake of acrylamide were calculated. The average exposure to acrylamide from the investigated dietary products was found to be 5 times higher than the intake of 0.08 µg/kg-bw/day, as estimated by the NFCA (Norwegian Food Control Authority) and 3 times higher than the intake of 0.14 µg/kg-bw/day as set by the WHO (World Health Organization). MOEN and MOEC (Margin of Exposure for neurotoxic and carcinogenic risks) values ranged between 290 and 556, and between 449 and 861 respectively. Kaak, Crackers, and Toast appear to pose no neurotoxic or carcinogenic risk of concern among the entire population as well as the individual age groups. French bread and Lebanese bread pose different levels of carcinogenic risk among the entire population as well as various age groups. The results also indicate that 24% of children, 4% of young adults and 8% of adults are at both neurotoxic and carcinogenic risks.


Asunto(s)
Acrilamida , Síndromes de Neurotoxicidad , Acrilamida/toxicidad , Pan/análisis , Carcinógenos/toxicidad , Niño , Cromatografía Liquida , Contaminación de Alimentos/análisis , Humanos , Espectrometría de Masas en Tándem , Adulto Joven
6.
Sci Rep ; 12(1): 6065, 2022 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-35410347

RESUMEN

The JmjC family of 2-oxoglutarate dependent oxygenases catalyse a range of hydroxylation and demethylation reactions in humans and other animals. Jumonji domain-containing 7 (JMJD7) is a JmjC (3S)-lysyl-hydroxylase that catalyses the modification of Developmentally Regulated GTP Binding Proteins 1 and 2 (DRG1 and 2); JMJD7 has also been reported to have histone endopeptidase activity. Here we report biophysical and biochemical studies on JMJD7 from Drosophila melanogaster (dmJMJD7). Notably, crystallographic analyses reveal that the unusual dimerization mode of JMJD7, which involves interactions between both the N- and C-terminal regions of both dmJMJD7 monomers and disulfide formation, is conserved in human JMJD7 (hsJMJD7). The results further support the assignment of JMJD7 as a lysyl hydroxylase and will help enable the development of selective inhibitors for it and other JmjC oxygenases.


Asunto(s)
Drosophila melanogaster , Histona Demetilasas con Dominio de Jumonji , Animales , Drosophila melanogaster/metabolismo , Histonas/metabolismo , Humanos , Hidroxilación , Histona Demetilasas con Dominio de Jumonji/metabolismo , Oxigenasas/metabolismo
7.
Commun Biol ; 4(1): 1243, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34725432

RESUMEN

Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a 'gain-of-function' to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation. Mg2+/Mn2+ ions enhance substrate binding to wt IDH1 and R132H IDH1, but with the former manifesting lower Mg2+/Mn2+ KMs. The isocitrate-Mg2+ complex is the preferred wt IDH1 substrate; with R132H IDH1, separate and weaker binding of 2-oxoglutarate and Mg2+ is preferred. Binding of R132H IDH1 inhibitors at the dimer interface weakens binding of active site Mg2+ complexes; their potency is affected by the Mg2+ concentration. Inhibitor selectivity for R132H IDH1 over wt IDH1 substantially arises from different stabilities of wt and R132H IDH1 substrate-Mg2+ complexes. The results reveal the importance of substrate-metal ion complexes in wt and R132H IDH1 catalysis and the basis for selective R132H IDH1 inhibition. Further studies on roles of metal ion complexes in TCA cycle and related metabolism, including from an evolutionary perspective, are of interest.


Asunto(s)
Variación Genética , Isocitrato Deshidrogenasa/genética , Magnesio/metabolismo , Manganeso/metabolismo , Iones/metabolismo , Isocitrato Deshidrogenasa/metabolismo , Oncogenes
8.
J Phys Chem Lett ; 12(26): 6095-6101, 2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34170697

RESUMEN

Human isocitrate dehydrogenase (IDH1) and its cancer-associated variant (IDH1 R132H) are rendered electroactive through coconfinement with a rapid NADP(H) recycling enzyme (ferredoxin-NADP+ reductase) in nanopores formed within an indium tin oxide electrode. Efficient coupling to localized NADP(H) enables IDH activity to be energized, controlled, and monitored in real time, leading directly to a thermodynamic redox landscape for accumulation of the oncometabolite, 2-hydroxyglutarate, that would occur in biological environments when the R132H variant is present. The technique enables time-resolved, in situ measurements of the kinetics of binding and dissociation of inhibitory drugs.


Asunto(s)
Enzimas , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Nanotecnología/instrumentación , Neoplasias/genética , Electrodos , Humanos , Cinética , Neoplasias/enzimología , Oxidación-Reducción , Termodinámica
9.
Sci Rep ; 10(1): 21964, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33319810

RESUMEN

Crystallization is the bottleneck in macromolecular crystallography; even when a protein crystallises, crystal packing often influences ligand-binding and protein-protein interaction interfaces, which are the key points of interest for functional and drug discovery studies. The human hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) readily crystallises as a homotrimer, but with a sterically blocked active site. We explored strategies aimed at altering PHD2 crystal packing by protein modification and molecules that bind at its active site and elsewhere. Following the observation that, despite weak inhibition/binding in solution, succinamic acid derivatives readily enable PHD2 crystallization, we explored methods to induce crystallization without active site binding. Cyclic peptides obtained via mRNA display bind PHD2 tightly away from the active site. They efficiently enable PHD2 crystallization in different forms, both with/without substrates, apparently by promoting oligomerization involving binding to the C-terminal region. Although our work involves a specific case study, together with those of others, the results suggest that mRNA display-derived cyclic peptides may be useful in challenging protein crystallization cases.


Asunto(s)
Prolina Dioxigenasas del Factor Inducible por Hipoxia/química , Péptidos Cíclicos/química , Secuencia de Aminoácidos , Cristalización , Humanos , Ligandos , Modelos Moleculares , Unión Proteica , Homología de Secuencia de Aminoácido
10.
J Biol Chem ; 295(49): 16545-16561, 2020 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-32934009

RESUMEN

In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.


Asunto(s)
Dictyostelium/enzimología , Prolil Hidroxilasas/metabolismo , Proteínas Protozoarias/metabolismo , Toxoplasma/enzimología , Secuencia de Aminoácidos , Animales , Sitios de Unión , Biocatálisis , Cristalografía por Rayos X , Humanos , Hidroxilación , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Cinética , Simulación de Dinámica Molecular , Oxígeno/metabolismo , Prolil Hidroxilasas/química , Prolil Hidroxilasas/genética , Estructura Terciaria de Proteína , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , Proteínas Quinasas Asociadas a Fase-S/química , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Alineación de Secuencia , Especificidad por Sustrato
13.
Commun Biol ; 3(1): 247, 2020 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32433536

RESUMEN

Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes and identifying new diagnostic, prognostic, and therapeutic targets. Comprehensive and robust analysis of primary metabolic pathways in cells, tissues and bio-fluids, remains technically challenging. We report on the development and validation of a highly reproducible and robust untargeted method using anion-exchange tandem mass spectrometry (IC-MS) that enables analysis of 431 metabolites, providing detailed coverage of central carbon metabolism. We apply the method in an untargeted, discovery-driven workflow to investigate the metabolic effects of isocitrate dehydrogenase 1 (IDH1) mutations in glioblastoma cells. IC-MS provides comprehensive coverage of central metabolic pathways revealing significant elevation of 2-hydroxyglutarate and depletion of 2-oxoglutarate. Further analysis of the data reveals depletion in additional metabolites including previously unrecognised changes in lysine and tryptophan metabolism.


Asunto(s)
Cromatografía por Intercambio Iónico , Glutaratos/metabolismo , Isocitrato Deshidrogenasa/genética , Ácidos Cetoglutáricos/metabolismo , Mutación , Espectrometría de Masas en Tándem , Línea Celular Tumoral , Glioblastoma , Humanos , Redes y Vías Metabólicas
15.
ChemMedChem ; 15(3): 270-273, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-31751494

RESUMEN

The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure-activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors.


Asunto(s)
Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Inhibidores de Prolil-Hidroxilasa/farmacología , Pirimidinonas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Prolil-Hidroxilasa/química , Pirimidinonas/química , Relación Estructura-Actividad
16.
Elife ; 82019 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-31500697

RESUMEN

Human and other animal cells deploy three closely related dioxygenases (PHD 1, 2 and 3) to signal oxygen levels by catalysing oxygen regulated prolyl hydroxylation of the transcription factor HIF. The discovery of the HIF prolyl-hydroxylase (PHD) enzymes as oxygen sensors raises a key question as to the existence and nature of non-HIF substrates, potentially transducing other biological responses to hypoxia. Over 20 such substrates are reported. We therefore sought to characterise their reactivity with recombinant PHD enzymes. Unexpectedly, we did not detect prolyl-hydroxylase activity on any reported non-HIF protein or peptide, using conditions supporting robust HIF-α hydroxylation. We cannot exclude PHD-catalysed prolyl hydroxylation occurring under conditions other than those we have examined. However, our findings using recombinant enzymes provide no support for the wide range of non-HIF PHD substrates that have been reported.


Asunto(s)
Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Péptidos/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Recombinantes/metabolismo , Hidroxilación , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Oxígeno/metabolismo , Proteínas Recombinantes/genética , Especificidad por Sustrato
17.
ACS Chem Biol ; 14(8): 1737-1750, 2019 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-31287655

RESUMEN

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox might provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.


Asunto(s)
Deferasirox/farmacología , Inhibidores Enzimáticos/farmacología , Quelantes del Hierro/farmacología , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Dominio Catalítico/efectos de los fármacos , Línea Celular Tumoral , Desmetilación/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Histonas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/química
18.
Bioorg Med Chem ; 27(12): 2405-2412, 2019 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-30737136

RESUMEN

The hydroxylation of prolyl-residues in eukaryotes is important in collagen biosynthesis and in hypoxic signalling. The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are drug targets for the treatment of anaemia, while the procollagen prolyl hydroxylases and other 2-oxoglutarate dependent oxygenases are potential therapeutic targets for treatment of cancer, fibrotic disease, and infection. We describe assay development and inhibition studies for a procollagen prolyl hydroxylase from Paramecium bursaria chlorella virus 1 (vCPH). The results reveal HIF PHD inhibitors in clinical trials also inhibit vCPH. Implications for the targeting of the human PHDs and microbial prolyl hydroxylases are discussed.


Asunto(s)
Procolágeno-Prolina Dioxigenasa/química , Inhibidores de Prolil-Hidroxilasa/química , Pruebas de Enzimas , Hidroxilación , Prolina Dioxigenasas del Factor Inducible por Hipoxia/química , Ácidos Cetoglutáricos/química , Oligopéptidos/química , Phycodnaviridae/enzimología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
19.
ChemMedChem ; 14(1): 94-99, 2019 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-30380199

RESUMEN

Prolyl hydroxylation domain (PHD) enzymes catalyze the hydroxylation of the transcription factor hypoxia-inducible factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue-protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1-chloro-4-hydroxybenzo[g]isoquinoline-3-carbonyl)glycine which is suited to fluorescence-based detection assays and for monitoring PHD inhibitors in biological systems. In cell-based assays, application of the fluorescent PHD inhibitor allowed co-localization with a cellular PHD enzyme and led to live cell imaging of processes involved in cellular oxygen sensing.


Asunto(s)
Bencilisoquinolinas/farmacología , Colorantes Fluorescentes/farmacología , Imagen Molecular/métodos , Imagen Óptica/métodos , Prolil Hidroxilasas/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Bencilisoquinolinas/síntesis química , Bencilisoquinolinas/química , Biocatálisis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Prolil-Hidroxilasa/síntesis química , Inhibidores de Prolil-Hidroxilasa/química , Relación Estructura-Actividad
20.
Chemistry ; 25(8): 2019-2024, 2019 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-30427558

RESUMEN

Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template-based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2.


Asunto(s)
Prolil Hidroxilasas , Inhibidores de Prolil-Hidroxilasa , Ribosomas/efectos de los fármacos , Proteínas Portadoras/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Proteínas Nucleares/antagonistas & inhibidores , Prolil Hidroxilasas/metabolismo , Inhibidores de Prolil-Hidroxilasa/química , Inhibidores de Prolil-Hidroxilasa/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Ribosomas/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato
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