A5022437232- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Protein purification and stability
- Protein Structure and Dynamics
- Advanced NMR Techniques and Applications
- biodegradable polymer synthesis and properties
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- Advanced Chemical Physics Studies
- Molecular spectroscopy and chirality
- Analytical Chemistry and Chromatography
- Computational Drug Discovery Methods
- Electron Spin Resonance Studies
- Enzyme Structure and Function
- Biopolymer Synthesis and Applications
- Conducting polymers and applications
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- X-ray Diffraction in Crystallography
- Amino Acid Enzymes and Metabolism
- Mitochondrial Function and Pathology
- Hydrogels: synthesis, properties, applications
- Solid-state spectroscopy and crystallography
- RNA modifications and cancer
- Viral Infectious Diseases and Gene Expression in Insects
Johnson & Johnson (United States)
2024
Pfizer (United States)
2020-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
2014-2022
Max Planck Institute for Biophysical Chemistry
2006-2013
Max Planck Society
2005-2013
National University of Rosario
2007
Instituto de Biología Molecular y Celular de Rosario
2007
Université Joseph Fourier
2007
Centre National de la Recherche Scientifique
2007
Université Grenoble Alpes
2007
Increasing evidence suggests that phosphorylation may play an important role in the oligomerization, fibrillogenesis, Lewy body (LB) formation, and neurotoxicity of α-synuclein (α-syn) Parkinson disease. Herein we demonstrate α-syn is phosphorylated at S87 vivo within LBs. The levels S87-P are increased brains transgenic (TG) models synucleinopathies human from Alzheimer disease (AD), LB (LBD), multiple system atrophy (MSA) patients. Using antibodies against (S129-P S87-P), a significant...
Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest drugging ncRNA with small molecules. The recent discovery ribocil, a structurally distinct synthetic mimic natural ligand flavin mononucleotide (FMN) riboswitch, has revealed potential chemical diversity molecules that target ncRNA. Affinity-selection mass spectrometry (AS-MS) is theoretically applicable high-throughput screening (HTS) binding Here, we report first application Automated...
The relation of alpha-synuclein (alphaS) aggregation to Parkinson's disease has long been recognized, but the pathogenic species and its molecular properties have yet be identified. To obtain insight into alphaS in an aggregation-prone state, we studied structural at acidic pH using NMR spectroscopy computation. demonstrated that remains natively unfolded lower pH, secondary structure propensities were changed proximity residues. ensemble conformations is characterized by a rigidification...
Ni/photoredox (4DPAIPN) dual catalysis enabled challenging peptide C(sp2)-O coupling reactions. Successful cross-coupling reactions were demonstrated with highly functionalized alcohols including side chains of amino acids (i.e., serine, threonine, tyrosine), trans-4-hydroxy-l-proline, alkyl alcohols, alkynylated and carbohydrates. Coupling between bromobenzoyl-capped peptides containing various either a protected serine building block or serine-containing dipeptide also proceeded...
Natively unfolded proteins play key roles in normal and pathological biochemical processes. This category of remains, however, beyond the reach classical structural biology because their inherent conformational heterogeneity. When confined weakly aligning media, natively such as α-synuclein, major component abnormal aggregates brain patients with Parkinson's disease, display surprisingly variable NMR dipolar couplings a function position along chain, suggesting presence residual secondary or...
Many neurodegenerative disorders are associated with the deposition of amyloid fibrils. Aggregation is generally initiated by unfolding native state aggregating protein, then conversion into a β-sheet-rich architecture. Using solution- and solid-state NMR spectroscopy, we show that secondary structure α-synuclein fibrils, major component deposits in Parkinson's disease, correlates directly structural properties unfolded state. Supporting information for this article available on WWW under...
The action of arginase, a metalloenzyme responsible for the hydrolysis arginine to urea and ornithine, is hypothesized suppress immune-cell activity within tumor microenvironment, thus its inhibition may constitute means by which potentiate efficacy immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme–inhibitor cocrystal structures, we designed synthesized novel inhibitors human arginase possessing fused 5,5-bicyclic ring system. prototypical...
With the emergence and rapid spreading of NDM-1 existence clinically relevant VIM-1 IMP-1, discovery pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with fragment high-throughput screenings, we performed a knowledge-based search known metallo-beta-lactamase (MBLIs) to identify starting points for early engagement medicinal chemistry. A class compounds exemplified by 11, discovered earlier as B. fragilis inhibitors,...
Out in the cold: Amyloid fibrils formed by protein α-synuclein, one of key players Parkinson's disease, are rapidly dissociated supercooled water at −15 °C (see TEM images), conditions which many globular proteins remain folded. NMR studies indicate that weakening hydrophobic and electrostatic interactions contribute to cold-induced destabilization amyloid fibrils.
The major component of neural inclusions that are the pathological hallmark Parkinson's disease amyloid fibrils protein α-synuclein (aS). Here we investigated if disease-related mutation A30P not only modulates kinetics aS aggregation, but also alters structure fibrils. To this end optimized method quenched hydrogen/deuterium exchange coupled to NMR spectroscopy and performed two-dimensional proton-detected high-resolution magic angle spinning experiments. combined data indicate does cause...
Long-range structural information derived from paramagnetic relaxation enhancement observed in the presence of a nitroxide radical is highly useful for characterization globular, modular and intrinsically disordered proteins, as well protein–protein protein-DNA complexes. Here we characterized conformation spin-label attached to homodimeric protein CylR2 using combination X-ray crystallography, electron resonance (EPR) NMR spectroscopy. Close agreement was found between spin label crystal...
Characterizing changes in the higher order structure (HOS) of monoclonal antibodies upon stressed conditions is critical to gaining a better understanding product and process. One single biophysical approach may not be best suited assess HOS comprehensively; thus, synergy from multiple, complementary approaches improves characterization accuracy resolution. In this study, we employed two mass spectrometry (MS )-based footprinting techniques, namely, fast photochemical oxidation proteins...
Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with high degree three-dimensionality. The analogs that favored the Cγ-exo conformation proline improved potency over initial lead. novel reported here not only enable access to previously unknown stereochemically complex derivatives but also provide foundation for future synthesis analogs, which incorporate inherent three-dimensional character into building...
CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development unwanted immune response against biotherapeutics, such as generation anti-drug antibodies (ADA). Therefore, identification HLAII-presented derived from biotherapeutics crucial part immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous epitopes have been identified by HLAII immunopeptidomics antibody-based using...
Abstract Purpose Nuclear magnetic resonance (NMR) spectroscopy provides the sensitivity and specificity to probe higher order structure (HOS) of monoclonal antibodies (mAbs) for potential changes. This study demonstrates an application chemometric tools measure differences in NMR spectra mAbs after forced degradation relative respective unstressed starting materials. Methods Samples adalimumab (Humira, ADL-REF) trastuzumab (Herceptin, TRA-REF) were incubated three buffer-pH conditions at...
Conformational changes are essential for protein-protein and protein-ligand recognition. Here we probed in the structure of protein ubiquitin at low temperatures supercooled water using NMR spectroscopy. We demonstrate that is well folded down to 263 K, although slight rearrangements hydrophobic core occur. However, amide proton chemical shifts show non-linear temperature dependence solution backbone hydrogen bonds become weaker region most prone cold-denaturation. Our data suggest weakening...