A5060896107- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Amyotrophic Lateral Sclerosis Research
- Alzheimer's disease research and treatments
- Synthesis and Biological Evaluation
- Cytomegalovirus and herpesvirus research
- Chemical Synthesis and Analysis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Wnt/β-catenin signaling in development and cancer
- Parkinson's Disease Mechanisms and Treatments
- SARS-CoV-2 and COVID-19 Research
- Research on Leishmaniasis Studies
- Computational Drug Discovery Methods
- Adenosine and Purinergic Signaling
- COVID-19 Clinical Research Studies
- Genetics and Neurodevelopmental Disorders
- Mast cells and histamine
- Click Chemistry and Applications
- Synthesis and Characterization of Heterocyclic Compounds
- Nuclear Receptors and Signaling
- Receptor Mechanisms and Signaling
- Synthesis and biological activity
- Trypanosoma species research and implications
- Synthesis and Catalytic Reactions
- Neuroscience and Neuropharmacology Research
Centro de Investigaciones Biológicas Margarita Salas
2016-2025
Biomedical Research Networking Center on Neurodegenerative Diseases
2019-2025
Instituto de Salud Carlos III
2020-2025
Centro de Investigación Biomédica en Red
2020-2025
Consejo Superior de Investigaciones Científicas
2010-2024
Universidad de Santiago de Chile
2024
Universidad Autónoma de Chile
2024
Weatherford College
2008-2023
Biogipuzkoa Health Research Institute
2023
Unidades Centrales Científico-Técnicas
2020
Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses these energy-rich molecules have been developed. In recent times in particular, completely new perspectives developed for their use peptide chemistry, combinatorial and heterocyclic synthesis. Organic assumed an important position at interface between biology, medicine, materials science. this Review, fundamental characteristics azide chemistry current developments are presented. The focus will...
Abstract Seit der Entdeckung organischen Azide vor über einhundertvierzig Jahren durch Peter Grieß wurde eine Reihe von Synthesen für diese energiereichen Moleküle entwickelt. In letzter Zeit haben sich völlig neue Perspektiven Anwendungen in Peptidchemie, kombinatorischen Chemie und Heterocyclensynthese ergeben. Auf dem interdisziplinären Gebiet zwischen Chemie, Biologie, Medizin Materialwissenschaften nehmen organische inzwischen einen wichtigen Raum ein. diesem Aufsatz werden die...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS associated with alterations lipid metabolism. As its regulation occurs mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) emerging as crucial factor MAM formation and metabolism control. Using the MERLIN biosensor high-throughput screening within EU-OPENSCREEN ERIC, we discovered small...
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as regulator of glycogen metabolism but it also plays pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus the hippocampus, together with subventricular zone lateral ventricles, one regions which neurogenesis takes place adult brain. Here, using chemical genetic approach that involves use several diverse inhibitors GSK-3...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting muscle wasting, paralysis, death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion sporadic suggests new therapeutic targets pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive onset progression may result...
MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in different cellular functions that have emerged as key regulators neurodegenerative diseases such amyotrophic lateral sclerosis (ALS). ALS is fatal disease lacks not only effective treatments, but also presents delays its diagnosis, since reliable clinical biomarkers unavailable. In recent years, advancements high-throughput sequencing strategies led to the identification novel biomarkers, facilitating earlier diagnosis and...
Glycogen synthase kinase 3 (GSK-3) is an important drug target for human severe unmet diseases. Discovery and/or design of allosteric modulators are gaining importance in this field not only the increased selectivity kind compounds but also subtle modulation target. This last point utmost GSK-3 inhibition as a therapeutic approach. activity completely necessary life, and aberrant overactivity found pathologies should be inhibited with its inhibitors treatment. We performed here search...
Background Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP many cell types. This cyclic nucleotide key signal transduction wide variety cellular responses. In the brain, has been implicated learning, memory processes and other brain functions. Methodology/Principal Findings Here we show novel function phosphodiesterase inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, heterocyclic small molecule inhibitor 7,...
Glycogen synthase kinase 3 (GSK-3), a proline/serine protein ubiquitously expressed and involved in many cellular signaling pathways, plays key role the pathogenesis of Alzheimer's disease (AD) being probably link between β-amyloid tau pathology. A great effort has recently been done discovery development different new molecules, synthetic natural origin, able to inhibit this enzyme, several kinetics mechanisms binding have described. The small molecule called tideglusib belonging...
Cumulative evidence strongly supports that glycogen synthase kinase-3 (GSK-3) is a pathogenic molecule when it up-dysregulated, emerging as an important therapeutic target in severe unmet human diseases. GSK-3 specific inhibitors might be promising effective drugs for the treatment of devastating pathologies such neurodegenerative diseases, stroke, and mood disorders. As has ability to phosphorylate primed substrates, small molecules able bind this site should perfect drug candidates,...
The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that able to cross the blood-brain barrier. We previously found intraperitoneal treatment with exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). objective of this study was investigate neurogenic and cellular effects oral administration on amyloid β (Aβ) overload.We orally administered PDE7 (15 mg/kg/day) or vehicle 6-month-old mice. After 5 weeks treatment, we evaluated...
Mutations in the progranulin gene (GRN) are most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). pathology is characterized by hyperphosphorylation protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate directly. Previous works from our laboratory described presence CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation lymphoblast FTLD-TDP patients carriers a loss-of function mutation GRN (c.709-1G > A)....
Abstract Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization nuclear protein TDP-43 (TAR DNA-binding 43) in cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) able to phosphorylate TDP-43. Here, preclinical efficacy benzothiazole-based inhibitor IGS-2.7, both (A315T) transgenic mouse human...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications promote its aggregation the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates cellular animal models; thus, TTBK1 inhibitors emerge as promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase–ligand complex structure determination,...
African swine fever virus (ASFV) infectious cycle starts with the viral adsorption and entry into host cell. Then, is internalized via clathrin/dynamin mediated endocytosis macropinocytosis. Similar to other viruses, ASF virion then incorporated endocytic pathway. While endosomal maturation entails luminal acidification, decrease in pH acts on multilayer structure of dissolving outer capsid. Upon decapsidation, inner membrane exposed interact limiting late endosome for fusion. Viral fusion...
Development of kinase-targeted therapies for central nervous system (CNS) diseases is a great challenge. Glycogen synthase kinase 3 (GSK-3) offers potential severe CNS unmet diseases, being one the inhibitors on clinical trials different tauopathies. Following our hypothesis based enhanced reactivity residue Cys199 in binding site GSK-3, we examine here suitability phenylhalomethylketones as irreversible inhibitors. Our data confirm that halomethylketone unit essential inhibitory activity....