A5045173175- Amyloidosis: Diagnosis, Treatment, Outcomes
- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Peptidase Inhibition and Analysis
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Retinoids in leukemia and cellular processes
- Trace Elements in Health
- Bioinformatics and Genomic Networks
- Per- and polyfluoroalkyl substances research
- Chemical Synthesis and Analysis
- thermodynamics and calorimetric analyses
- Effects and risks of endocrine disrupting chemicals
- Vanadium and Halogenation Chemistry
- Drug Transport and Resistance Mechanisms
- Cholinesterase and Neurodegenerative Diseases
- S100 Proteins and Annexins
Institute of Advanced Chemistry of Catalonia
2020-2022
Universitat Ramon Llull
2013-2020
Institut Químic de Sarrià
2013-2020
Consejo Superior de Investigaciones Científicas
2020
Instituto de Química Orgánica General
2020
Universitat Pompeu Fabra
2013
Municipal Institute for Medical Research
2013
Hospital del Mar Research Institute
2013
Transthyretin (TTR) modulates the deposition, processing, and toxicity of Abeta (Aβ) peptides. We have shown that this effect is enhanced in mice by treatment with small molecules such as iododiflunisal (IDIF, 4), a good TTR stabilizer. Here, we describe thermodynamics formation binary ternary complexes among TTR, Aβ(1–42) peptide, stabilizers using isothermal titration calorimetry (ITC). A TTR/Aβ(1–42) (1:1) complex dissociation constant Kd = 0.94 μM formed; IDIF (4), improves up to 0.32...
Transthyretin (TTR) has a well-established role in neuroprotection Alzheimer's Disease (AD). We have setup drug discovery program of small-molecule compounds that act as chaperones enhancing TTR/Amyloid-beta peptide (Aβ) interactions. A combination computational repurposing approaches and vitro biological assays resulted set molecules which were then screened with our in-house validated high-throughput screening ternary test. prioritized list was obtained corroborated ITC studies....
Several strategies against Alzheimer disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating TTR-Aβ interaction have been previously studied. Herein, key structural features between Aβ(12-28) peptide (3), essential recognition element Aβ, unravelled STD-NMR spectroscopy methods in solution. Molecular aspects related role stabilizer iododiflunisal (IDIF, 5) on complex also...
Several anthropogenic contaminants have been identified as competing with the thyroid hormone thyroxine (T4) for binding to transport proteins transthyretin (TTR). This can potentially create toxicity mechanisms posing a threat human health. Many organic UV filters (UVFs) and paraben preservatives (PBs), widely used in personal care products, are chemicals of emerging concern due their adverse effects potential thyroid-disrupting compounds. Recently, UVFs found paired maternal fetal samples...
The amyloidogenic protein transthyretin (TTR) is thought to aggregate into amyloid fibrils by tetramer dissociation which can be inhibited a number of small molecule compounds. Our analysis series crystallographic protein-inhibitor complexes has shown no clear correlation between the observed molecular interactions and in vitro activity inhibitors. From this analysis, it emerged that halogen bonding (XB) could mediating some key interactions. Analysis halogenated derivatives two well-known...
Abstract It is well settled that the amyloidogenic properties of plasma protein transporter transthyretin (TTR) can be modulated by compounds stabilize its native tetrameric conformation. TTR also present in cerebrospinal fluid where it bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown treatment Alzheimer’s Disease (AD) model mice with iododiflunisal (IDIF), a tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as new lead drug for AD....
Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer therapeutic strategy for these diseases. Tafamidis, only approved drug FAP treatment, not effective all patients. Herein, we discovered that benzbromarone (BBM), uricosuric drug, an stabilizer and inhibitor against fibril formation. BBM rendered more resistant to urea denaturation, similarly iododiflunisal...
Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer's disease.We monitored the therapeutic efficacy two stabilizers, iododiflunisal (IDIF), acts small-molecule chaperone interaction, and tolcapone, does not behave chaperone, an animal model disease using positron emission...
Human transthyretin (hTTR), a serum protein with main role in transporting thyroid hormones and retinol through binding to the retinol-binding protein, is an amyloidogenic involved familial amyloidotic polyneuropathy (FAP), cardiomyopathy, central nervous system selective amyloidosis. hTTR also has neuroprotective Alzheimer disease, being major Aβ human cerebrospinal fluid (CSF) that prevents amyloid-β (Aβ) aggregation consequent abrogation of toxicity. Here we report optimized preparative...
Abstract The protein transthyretin (TTR) modulates amyloid‐β (Aβ) peptides deposition and processing this physiological effect is further enhanced by treatment with iododiflunisal (IDIF), a small‐molecule compound (SMC) TTR tetramer stabilization properties, which behaves as chaperone of the complex. This knowledge has prompted us to design optimize rapid simple high‐throughput assay that relies on ability test compounds form ternary soluble complexes TTR/Aβ/SMC prevent Aβ aggregation....
Abstract Background: Transthyretin (TTR) is a tetrameric, Amyloid-beta (Aβ)-binding protein, which has been shown to reduce Aβ toxicity both in vitro and vivo. The ability of TTR interact with can be enhanced by series small molecules that stabilize its tetrameric form. Because this, stabilizers might act as disease modifying drugs Alzheimer Disease (AD). In this work, we monitored the therapeutic efficacy two stabilizers, iododiflunisal (IDIF) repurposed drug tolcapone, longitudinal...
Transthyretin (TTR) has a well-established role in neuroprotection, evidenced Alzheimer’s Disease (AD). By targeting TTR we have setup drug discovery program of small-molecule compounds that act as chaperones, enhancing TTR/ amyloid-β peptide (Aβ) interactions. In first stage, carried out two computational repurposing approaches. second the computationally selected were assessed for their ability to bind and stabilize tetramer, using thyroxine displacement tests, by assessing level monomers,...
Transthyretin (TTR) has a well-established role in neuroprotection, evidenced Alzheimer’s Disease (AD). By targeting TTR we have setup drug discovery program of small-molecule compounds that act as chaperones, enhancing TTR/ amyloid-β peptide (Aβ) interactions. In first stage, carried out two computational repurposing approaches. second the computationally selected were assessed for their ability to bind and stabilize tetramer, using thyroxine displacement tests, by assessing level monomers,...