A5085832939- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Photochromic and Fluorescence Chemistry
- Photoreceptor and optogenetics research
- Glycosylation and Glycoproteins Research
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Trypanosoma species research and implications
- Biochemical and Molecular Research
- Cellular transport and secretion
- Chemical Synthesis and Analysis
- Porphyrin and Phthalocyanine Chemistry
- Tuberculosis Research and Epidemiology
- Cytomegalovirus and herpesvirus research
- Retinal Development and Disorders
- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Luminescence and Fluorescent Materials
- Calcium signaling and nucleotide metabolism
- Synthesis and Catalytic Reactions
- Asymmetric Hydrogenation and Catalysis
- Chemical Reactions and Isotopes
- HIV/AIDS drug development and treatment
- Neuropeptides and Animal Physiology
- Natural Antidiabetic Agents Studies
Institute for Bioengineering of Catalonia
2016-2023
Universidade Federal de São Paulo
2023
Institute of Advanced Chemistry of Catalonia
2011-2020
University of Cambridge
2018-2019
Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine
2018
Consejo Superior de Investigaciones Científicas
2011
Abstract Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors methods for covalent attachment depend genetic manipulation. Here we introduce a chemical strategy covalently conjugate photoswitch the of proteins demonstrate its application kainate receptor channel GluK1. The approach is photoswitchable...
GPCRs play critical roles in cell communication. Although can form heteromers, their role signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit. mGluRs both constitutive homo- and heterodimers. Whereas mGlu2 mGlu4 couple G proteins, protein activation is mediated by heptahelical domain (HD) exclusively mGlu2-4 Such asymmetric transduction results from action of dimeric extracellular...
Tuberculosis (TB) remains a major cause of mortality worldwide, and improved treatments are needed to combat emergence drug resistance. Inosine 5′-monophosphate dehydrogenase (IMPDH), crucial enzyme required for de novo synthesis guanine nucleotides, is an attractive TB target. Herein, we describe the identification potent IMPDH inhibitors using fragment-based screening structure-based design techniques. Screening fragment library Mycobacterium thermoresistible (Mth) ΔCBS identified low...
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Current therapeutic options show limited efficacy and do not treat some important aspects disease. Therefore, it may be advantageous to identify strategies that could improve existing treatments. Pharmacological chaperones are small molecules protect proteins from degradation, their use in combination with replacement therapy (ERT) has been proposed as...
A molecular-diversity-oriented approach for the preparation of bicyclic sp2-iminosugar glycomimetics related to nojirimycin and galactonojirimycin is reported. The synthetic strategy takes advantage ability endocyclic pseudoamide-type atoms in five-membered cyclic iso(thio)ureas guanidines undergo intramolecular nucleophilic addition masked carbonyl group monosaccharides. stereochemistry resulting hemiaminal stereocenter governed by anomeric effect, with a large preference axial (pseudo-α)...
Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, compounds enhanced GCase activity at very low concentrations. The most inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) 1 nM isolated and an IC(50) 4.3 when assayed human fibroblast...
Four diastereomeric series of N-alkylated [6+5] bicyclic isoureas having hydroxyl substituents mimicking glucose groups have been synthesized as potential β-glucocerebrosidase (GCase) inhibitors with the aim developing pharmacological chaperones for enzyme deficiency in Gaucher disease (GD). The compounds differ either by configuration ring fusion carbon atoms or nature N-alkyl substituents. When assayed effects on GCase activity, displayed selective inhibition low micromolar to nanomolar...
A series of cyclitol derivatives with myo-configuration are β-glucocerebrosidase (GCase) inhibitors and show excellent characteristics for the development pharmacological chaperones enzyme deficiency in Gaucher disease (GD). The most potent inhibitor, (1S,2R,3R,4S,5R,6S)-5,6-bis(nonylamino)cyclohexane-1,2,3,4-tetraol, displayed a Ki value 26 nM isolated also inhibited GCase wild-type (wt) human fibroblasts at nanomolar concentrations. This diaminocyclitol produced maximum increases...
Four series of C7N aminocyclitol analogues glucose were synthesized by stereocontrolled epoxide opening hydroxyl protected forms the cyclohexane epoxides cyclophellitol and 1,6-epi-cyclophellitol. The resulting hydroxymethyl substituted aminocyclitols tested as glycosidase inhibitors. Cyclitols having an amino group in α configuration at a position equivalent to anomeric sugar found be low micromolar inhibitors α-glucosidase from baker's yeast with Ki's near 2 μM. On other hand, N-octyl...
A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors Aspergillus oryzae and Escherichia coliβ-galactosidases.
Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses have become attractive targets for drug therapy treat certain neurological disorders. However, high degree of sequence conservation around binding site makes development subtype-specific orthosteric ligands difficult achieve. This problem can be...
Gaucher disease (GD), resulting from deficient lysosomal enzyme β-glucosidase (GCase) activity, is the most common storage disorder. We have previously shown that aminocyclitol derivatives displayed selective inhibition of GCase and enhanced activity in N370S L444P at very low concentrations. In present study, we combined amino-myo-inositol amino-scyllo-inositol cores with a hydrophobic alkyl adamantyl amide to afford novel small molecules ability increase GD lymphoblasts. The potent...
We've combined the pharmacological properties of dynamin inhibitor dynasore and photochromic an azobenzene group, to obtain first light-regulated small-molecule endocytosis.
The active conformation of a family metabotropic glutamate receptor subtype 4 (mGlu4 ) positive allosteric modulators (PAMs) with the cyclohexane 1,2-dicarboxylic scaffold present in cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041) was investigated by testing structurally similar six-membered ring compounds that have locked conformation. norbornane and molecules designed as mGlu4 conformational probes enantiomers trans diastereomer were computationally characterized...
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A protocol for the reductive alkylation of unprotected aminocyclitols with supported reagents and scavengers is described. The method operatively simple provides corresponding secondary amines in high yields purities.
Background: Mucopolysaccharidosis Type 1 (MPS1) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Owing to limited efficacy current treatment options, pharmacological chaperone therapy (PCT) has been proposed as alternative therapeutic strategy. Therefore, it may be advantageous identify second-generation chaperones that protect IDUA from degradation without interfering with its activity.Methods: Using SEE-Tx® proprietary computational...