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1.
Hum Mol Genet ; 33(9): 818-834, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38641551

RESUMEN

Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.


Asunto(s)
Disqueratosis Congénita , Telomerasa , Humanos , Apoptosis/genética , ADN/metabolismo , Daño del ADN/genética , Disqueratosis Congénita/genética , Disqueratosis Congénita/metabolismo , Disqueratosis Congénita/patología , Mutación , Estrés Oxidativo/genética , ARN/genética , Telomerasa/genética , Telomerasa/metabolismo , Telómero/genética , Telómero/metabolismo
2.
Circ Res ; 134(8): e52-e71, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38497220

RESUMEN

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.


Asunto(s)
Síndrome de Andersen , Humanos , Ratones , Animales , Síndrome de Andersen/genética , Síndrome de Andersen/metabolismo , Mutación , Miocitos Cardíacos/metabolismo , Trastorno del Sistema de Conducción Cardíaco , Disulfuros , Fosfatidilinositoles/metabolismo
3.
Angew Chem Int Ed Engl ; 63(6): e202314595, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-37991081

RESUMEN

Lanthanides have unique photoluminescence (PL) emission properties, including very long PL lifetimes. This makes them ideal for biological imaging applications, especially using PL lifetime imaging microscopy (PLIM). PLIM is an inherently multidimensional technique with exceptional advantages for quantitative biological imaging. Unfortunately, due to the required prolonged acquisitions times, photobleaching of lanthanide PL emission currently constitutes one of the main drawbacks of PLIM. In this study, we report a small aqueous-soluble, lanthanide antenna, 8-methoxy-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinoline-3-phosphonic acid, PAnt, specifically designed to dynamically interact with lanthanide ions, serving as exchangeable dye aimed at mitigating photobleaching in PLIM microscopy in cellulo. Thus, self-assembled lanthanide complexes that may be photobleached during image acquisition are continuously replenished by intact lanthanide antennas from a large reservoir. Remarkably, our self-assembled lanthanide complex clearly demonstrated a significant reduction of PL photobleaching when compared to well-established lanthanide cryptates, used for bioimaging. This concept of exchangeable lanthanide antennas opens new possibilities for quantitative PLIM bioimaging.


Asunto(s)
Elementos de la Serie de los Lantanoides , Microscopía , Luminiscencia , Fotoblanqueo
4.
Actas Esp Psiquiatr ; 51(1): 1-8, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36912389

RESUMEN

The objective is to describe the problems related to outpatient psychogeriatric care in the context of the SARS-CoV-2 pandemic, as well as the proposed and implemented solutions for optimizing care for elderly people with mental disorders during the pandemic, that can also be applied in emerging similar situations in the future.


Asunto(s)
COVID-19 , Trastornos Mentales , Humanos , Anciano , SARS-CoV-2 , Psiquiatría Geriátrica , Trastornos Mentales/epidemiología , Pandemias
5.
Int J Mol Sci ; 23(4)2022 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-35216258

RESUMEN

Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics. Here, we evaluated the mechanical antinociceptive effect of IQM-PC332, a novel ligand of the multifunctional protein downstream regulatory element antagonist modulator (DREAM) in rats subjected to chronic constriction injury of the sciatic nerve as a model of neuropathic pain. IQM-PC332 administered by intraplantar (0.01-10 µg) or intraperitoneal (0.02-1 µg/kg) injection reduced mechanical sensitivity by ≈100% of the maximum possible effect, with ED50 of 0.27 ± 0.05 µg and 0.09 ± 0.01 µg/kg, respectively. Perforated-patch whole-cell recordings in isolated dorsal root ganglion (DRG) neurons showed that IQM-PC332 (1 and 10 µM) reduced ionic currents through voltage-gated K+ channels responsible for A-type potassium currents, low, T-type, and high voltage-activated Ca2+ channels, and transient receptor potential vanilloid-1 (TRPV1) channels. Furthermore, IQM-PC332 (1 µM) reduced electrically evoked action potentials in DRG neurons from neuropathic animals. It is suggested that by modulating multiple DREAM-ion channel signaling complexes, IQM-PC332 may serve a lead compound of novel multimodal analgesics.


Asunto(s)
Analgésicos/farmacología , Proteínas de Interacción con los Canales Kv/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Traumatismos de los Nervios Periféricos/complicaciones , Animales , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Ligandos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Neuralgia/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo
6.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-36012438

RESUMEN

The transient outward potassium current (Itof) is generated by the activation of KV4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (KV4.3/KChIP2, KV4.3/KChIP2/DPP6 or KV4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in KV4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing KV4.3/KChIP2 and KV4.3/KChIP2/KCNE2, but not in KV4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of KV4.3/KChIP2 channels to IQM-266.


Asunto(s)
Proteínas de Interacción con los Canales Kv , Canales de Potasio Shal , Animales , Cricetinae , Cricetulus , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/metabolismo , Técnicas de Placa-Clamp , Potasio/metabolismo , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismo
7.
Int J Mol Sci ; 22(3)2021 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-33572566

RESUMEN

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer's disease. KV4.x channels need to assemble with other accessory subunits (ß) to fully reproduce the ITO and ISA currents. ß Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Canalopatías/fisiopatología , Epilepsia/fisiopatología , Proteínas de Interacción con los Canales Kv/farmacología , Canales de Potasio con Entrada de Voltaje/farmacología , Esquizofrenia/fisiopatología , Canales de Potasio Shal/farmacología , Enfermedad de Alzheimer/etiología , Secuencia de Aminoácidos , Canalopatías/complicaciones , Epilepsia/etiología , Corazón/fisiopatología , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/metabolismo , Potenciales de la Membrana , Modelos Moleculares , Neuronas/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Esquizofrenia/etiología , Alineación de Secuencia , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismo
8.
Molecules ; 19(4): 4814-46, 2014 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-24743938

RESUMEN

A series of Phe-Gly dipeptide-derived piperazinones containing an aromatic urea moiety and a basic amino acid has been synthesized and evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cells. The synthetic strategy involves coupling of a protected basic amino acid benzyl amide to 1,2- and 1,2,4-substituted-piperazinone derivatives, through a carbonylmethyl group at the N1-position, followed by formation of an aromatic urea at the exocyclic moiety linked at the C2 position of the piperazine ring and removal of protecting groups. None of the compounds showed activity in the biological evaluation.


Asunto(s)
Dipéptidos/química , Peptidomiméticos/química , Piperazinas/química , Inhibidores de Agregación Plaquetaria/química , Receptor PAR-1/química , Humanos , Fragmentos de Péptidos/química , Peptidomiméticos/síntesis química , Agregación Plaquetaria , Inhibidores de Agregación Plaquetaria/síntesis química , Receptor PAR-1/antagonistas & inhibidores , Estereoisomerismo , Trombina/química , Urea/química
9.
ChemMedChem ; : e202400511, 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39387456

RESUMEN

The Spanish Society of Medicinal Chemistry (Sociedad Española de Química Terapéutica SEQT), founded in 1977, aims to advance pharmaceutical research and education in Spain, collaborating with academia, industry, and public entities. It was initially linked with the Institute of Medicinal Chemistry from Spanish National Research Council (IQM-CSIC), emphasizing the independence of medicinal chemistry as a discipline. SEQT's presidency rotates between representatives from universities, research institutes, and industry, ensuring diverse perspectives. With around 500 members, SEQT represents sectors including universities, CSIC, and industry, with a notable presence of early-career researchers. The Society actively participates in the European Federation for Medicinal chemistry and Chemical biology (EFMC). SEQT organizes conferences, summer schools, and mini symposia to facilitate networking and knowledge exchange among professionals. To support early-career scientists, SEQT organizes symposia and awards, recognizing achievements in drug discovery. It fosters mentorship opportunities and engages with international networks like EFMC-YSN. In 2023, SEQT established its Early Career Scientist (SEQT-ECS) group to provide tailored support and resources. With over 40 years of experience, SEQT continues to evolve, embracing social media and adapting to changes in medicinal chemistry and chemical biology. It remains committed to supporting its members and advancing research to address human health challenges.

10.
Spectrochim Acta A Mol Biomol Spectrosc ; 323: 124926, 2024 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-39116593

RESUMEN

Lanthanide photoluminescence (PL) emission has attracted much attention for technological and bioimaging applications because of its particularly interesting features, such as narrow emission bands and very long PL lifetimes. However, this emission process necessitates a preceding step of energy transfer from suitable antennas. While biocompatible applications require luminophores that are stable in aqueous media, most lanthanide-based emitters are quenched by water molecules. Previously, we described a small luminophore, 8-methoxy-2-oxo-1,2,4,5-tetrahydrocyclopenta[de]quinoline-3-phosphonic acid (PAnt), which is capable of dynamically coordinating with Tb(III) and Eu(III), and its exchangeable behavior improved their performance in PL lifetime imaging microscopy (PLIM) compared with conventional lanthanide cryptate imaging agents. Herein, we report an in-depth photophysical and time-dependent density functional theory (TD-DFT) computational study that reveals different sensitization mechanisms for Eu(III) and Tb(III) in stable complexes formed in water. Understanding this unique behavior in aqueous media enables the exploration of different applications in bioimaging or novel emitting materials.

11.
bioRxiv ; 2023 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-37333254

RESUMEN

Background: Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel. Methods and Results: We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1C122Y mutation. Kir2.1C122Y animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1C122Y mouse cardiomyocytes showed significantly reduced inward rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1C122Y formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP2) than WT. Therefore, consistent with the inability of Kir2.1C122Y channels to bind directly to PIP2 in bioluminescence resonance energy transfer experiments, the PIP2 binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP2 concentrations. Conclusion: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP2-dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.

12.
Pharmaceuticals (Basel) ; 14(10)2021 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-34681272

RESUMEN

SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against COVID-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here, we exploited the enormous potential of plant metabolism using the bryophyte Marchantia polymorpha L. and identified a potent SARS-CoV-2 antiviral, following a bioactivity-guided fractionation and mass-spectrometry approach. We found that the chlorophyll derivative Pheophorbide a (PheoA), a porphyrin compound similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2, preventing infection of cultured monkey and human cells, without noticeable cytotoxicity. We also show that PheoA targets the viral particle, interfering with its infectivity in a dose- and time-dependent manner. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against enveloped RNA viral pathogens such as HCV, West Nile, and other coronaviruses. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, which together with its previous use in photoactivable cancer therapy in humans, suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.

13.
Sci Rep ; 9(1): 7260, 2019 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-31086218

RESUMEN

DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on KV4.3 channel gating and blocked the ATF6/DREAM interaction. Our results validate DREAM as a valuable target and propose more effective molecules for HD treatment.


Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Proteínas de Interacción con los Canales Kv/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Proteínas Represoras/efectos de los fármacos , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Diseño de Fármacos , Humanos , Proteínas de Interacción con los Canales Kv/antagonistas & inhibidores , Ratones , Proteínas Represoras/antagonistas & inhibidores , Relación Estructura-Actividad
14.
Front Mol Neurosci ; 12: 11, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30787866

RESUMEN

Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents (I A). This effect is mediated by the interaction between DREAM and KV4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (I A) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of KV4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the KV4.3/DREAM current in a concentration-, voltage-, and time-dependent-manner. By decreasing the peak current and slowing the inactivation kinetics, IQM-266 led to an increase in the transmembrane charge ( Q K V 4.3 / DREAM ) at a certain range of concentrations. The slowing of the recovery process and the increase of the inactivation from the closed-state inactivation degree are consistent with a preferential binding of IQM-266 to a pre-activated closed state of KV4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of I A. Overall, the results presented here identify IQM-266 as a new chemical tool that might allow a better understanding of DREAM physiological role as well as modulation of neuronal I A in pathological processes.

15.
J Clin Invest ; 126(2): 627-38, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26752648

RESUMEN

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.


Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Cuerpo Estriado/metabolismo , Enfermedad de Huntington/metabolismo , Neuronas/metabolismo , Transducción de Señal , Factor de Transcripción Activador 6/genética , Animales , Células CHO , Carbamatos/farmacología , Cuerpo Estriado/patología , Cricetulus , Modelos Animales de Enfermedad , Células HEK293 , Células HeLa , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Proteínas de Interacción con los Canales Kv/genética , Proteínas de Interacción con los Canales Kv/metabolismo , Ratones , Neuronas/patología , Piperidinas/farmacología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
16.
Curr Top Med Chem ; 15(20): 2080-114, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25986685

RESUMEN

PAR1, member of the family of protease-activated receptors, is a GPCR whose activation requires a proteolytic cleavage at its extracellular N-terminus to unveil a tethered activating ligand. Although thrombin is the main activator of this receptor, diverse other proteases can also activate and disarm PAR1. Besides, tethered activating ligand-based peptides (PAR-APs) can also activate the receptor. PAR1 mainly signals via G proteins but, it can also signal using ß-arrestin pathways and by transactivation of other receptors. This complex PAR1 interactome is completed with the receptor desensitization, trafficking, and degradation. PAR1 has shown species-, cellular-, and physiological or pathological state-dependent specificity. This review try to give an overview on the complex PAR1 interactome, its therapeutic impact upon the cardiovascular, immune and nervous systems, inflammation and cancer, as well as, on its modulation with agonists and antagonists.


Asunto(s)
Arrestinas/química , Proteínas de Unión al GTP/química , Receptor PAR-1/química , Trombina/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ligandos , Neoplasias/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Especificidad de Órganos , Mapeo de Interacción de Proteínas , Transporte de Proteínas , Proteolisis , Receptor PAR-1/agonistas , Receptor PAR-1/antagonistas & inhibidores , Receptor PAR-1/genética , Transducción de Señal , Especificidad de la Especie , beta-Arrestinas
17.
J Med Chem ; 47(23): 5700-12, 2004 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-15509169

RESUMEN

With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl9-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl9-Pro8 amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.


Asunto(s)
Antineoplásicos/síntesis química , Depsipéptidos/síntesis química , Lactamas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Depsipéptidos/química , Depsipéptidos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/química , Lactamas/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Péptidos Cíclicos , Estructura Secundaria de Proteína , Relación Estructura-Actividad
18.
Eur J Med Chem ; 70: 199-224, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24158013

RESUMEN

A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2-oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N4-, N1-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at µM concentration. No correlation was observed between both types of activities.


Asunto(s)
Antineoplásicos/farmacología , Peptidomiméticos/farmacología , Piperazinas/farmacología , Receptor PAR-1/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Conformación Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Piperazinas/síntesis química , Piperazinas/química , Agregación Plaquetaria/efectos de los fármacos , Relación Estructura-Actividad
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