-
Nature Reviews. Drug Discovery Jul 2023Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural... (Review)
Review
Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a 'deuterium switch' approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed.
Topics: Humans; Deuterium; Drug Discovery; Chemistry, Pharmaceutical
PubMed: 37277503
DOI: 10.1038/s41573-023-00703-8 -
Cell Metabolism Jun 2024The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular...
The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular mechanisms. Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined with deuterium oxide (DO) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDs in tauopathy fly brains and human neurons derived from induced pluripotent stem cells (iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia induced LD accumulation, oxidative stress, inflammation, and impaired phagocytosis. Neuronal AMP-activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy in neurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathy mice increased LD accumulation, exacerbated pro-inflammatory microgliosis, and promoted neuropathology. Our findings provide direct evidence of native, aberrant LD accumulation in tauopathy brains and underscore the critical role of AMPK in regulating brain lipid homeostasis.
Topics: Animals; Lipid Droplets; Microglia; Humans; Mice; AMP-Activated Protein Kinases; Brain; Tauopathies; Neurons; Induced Pluripotent Stem Cells; Mice, Inbred C57BL; Male; Drosophila
PubMed: 38657612
DOI: 10.1016/j.cmet.2024.03.014 -
Journal of Labelled Compounds &... Oct 2023Created literally at the dawn of time, deuterium has been extremely valuable in so many chemistry roles. The subject of this review focuses on one deuterium application... (Review)
Review
Created literally at the dawn of time, deuterium has been extremely valuable in so many chemistry roles. The subject of this review focuses on one deuterium application in particular: its enhancement of luminescence in many substances. After providing general overviews of both deuterium and luminescence, the early exploration of deuterium's effect on luminescence is described, followed by a number of specific topics. These sections include a discussion of deuterium-influenced luminescence for dyes, proteins, singlet oxygen, and the lanthanide elements, as well as anomalous inverse deuterium luminescence effects. Future directions for this important research topic are also proposed, as well as a summary conclusion.
Topics: Luminescence; Deuterium; Singlet Oxygen
PubMed: 37587721
DOI: 10.1002/jlcr.4056 -
Frontiers in Molecular Biosciences 2023Thrombin is a serine protease that catalyzes a large number of different reactions including proteolytic cleave of fibrinogen to make the fibrin clot (procoagulant... (Review)
Review
Thrombin is a serine protease that catalyzes a large number of different reactions including proteolytic cleave of fibrinogen to make the fibrin clot (procoagulant activity), of the protease activated receptors (for cell signaling) and of protein C generating activated protein C (anticoagulant activity). Thrombin has an effector binding site called the anion binding exosite 1 that is allosterically coupled to the active site. In this review, we survey results from thermodynamic characterization of the allosteric coupling as well as hydrogen-deuterium exchange mass spectrometry to reveal which parts of the thrombin structure are changed upon effector binding and/or mutagenesis, and finally NMR spectroscopy to characterize the different timescales of motions elicited by the effectors. We also relate the experimental work to computational network analysis of the thrombin-thrombomodulin complex.
PubMed: 37457835
DOI: 10.3389/fmolb.2023.1200465 -
Organic Letters Dec 2023Stereoselective α-amino C-H epimerization of exocyclic amines is achieved via photoredox catalyzed, thiyl-radical mediated, reversible hydrogen atom transfer to provide...
Stereoselective α-amino C-H epimerization of exocyclic amines is achieved via photoredox catalyzed, thiyl-radical mediated, reversible hydrogen atom transfer to provide thermodynamically controlled anti/syn isomer ratios. The method is applicable to different substituents and substitution patterns about aminocyclopentanes, aminocyclohexanes, and a -Boc-3-aminopiperidine. The method also provided efficient epimerization for primary, alkyl and (hetero)aryl secondary, and tertiary exocyclic amines. Demonstration of reversible epimerization, deuterium labeling, and luminescence quenching provides insight into the reaction mechanism.
PubMed: 38114418
DOI: 10.1021/acs.orglett.3c03801 -
Molecular & Cellular Proteomics : MCP Aug 2023Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used...
Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; DO) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of "older" less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2'-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Proteome; Proteomics; Homeodomain Proteins; Myoblasts; Muscle, Skeletal
PubMed: 37353005
DOI: 10.1016/j.mcpro.2023.100605 -
Biomedicines Apr 2024The thymus provides maturation and migration of T cells to peripheral organs of immunity, where they recognize diverse antigens and maintain immunological memory and...
The thymus provides maturation and migration of T cells to peripheral organs of immunity, where they recognize diverse antigens and maintain immunological memory and self-tolerance. The thymus is known to be involved with age and in response to stress factors. Therefore, the search for approaches to the restoration of thymopoiesis is of great interest. The present investigation was aimed at evaluating how prolonged deuterium depletion affects morphogenetic processes and the physiological transition of the thymus to age-related involution. The study was performed on 60 male Wistar rats subjected to consumption of deuterium-depleted water with a 10 ppm deuterium content for 28 days. The control rats consumed distilled water with a normal deuterium content of 150 ppm. The examination found no significant differences in body weight gain or the amount of water consumed. The exposed rats exhibited similar to control dynamics of the thymus weight but significant changes in thymic cell maturation according to cytofluorimetric analysis of thymic subpopulations. Changes in T cell production were not monotonic and differentially engaged morphogenetic processes of cell proliferation, differentiation, and migration. The reactive response to deuterium depletion was a sharp increase in the number of progenitor CD4CD8 cells and their differentiation into T cells. The compensatory reaction was inhibition of thymopoiesis with more pronounced suppression of differentiation of T-cytotoxic lymphocytes, followed by intensification of emigration of mature T cells to the bloodstream. This period lasts from 3 to 14 days, then differentiation of thymic lymphocytes is restored, later cell proliferation is activated, and finally the thymopoiesis rate exceeds the control values. The increase in the number of thymic progenitor cells after 3-4 weeks suggests consideration of deuterium elimination as a novel approach to prevent thymus involution.
PubMed: 38790918
DOI: 10.3390/biomedicines12050956 -
Mass Spectrometry Reviews 2023The combined use of hydrogen/deuterium exchange (HDX) and mass spectrometry (MS), referred to as HDX-MS, is a powerful tool for exploring molecular edifices and has been... (Review)
Review
The combined use of hydrogen/deuterium exchange (HDX) and mass spectrometry (MS), referred to as HDX-MS, is a powerful tool for exploring molecular edifices and has been used for over 60 years. Initially for structural and mechanistic investigation of low-molecular weight organic compounds, then to study protein structure and dynamics, then, the craze to study small molecules by HDX-MS accelerated and has not stopped yet. The purpose of this review is to present its different facets with particular emphasis on recent developments and applications. Reversible H/D exchanges of mobilizable protons as well as stable exchanges of non-labile hydrogen are considered whether they are taking place in solution or in the gas phase, or enzymatically in a biological media. Some fundamental principles are restated, especially for gas-phase processes, and an overview of recent applications, ranging from identification to quantification through the study of metabolic pathways, is given.
Topics: Hydrogen Deuterium Exchange-Mass Spectrometry; Deuterium; Deuterium Exchange Measurement; Mass Spectrometry; Hydrogen
PubMed: 34859466
DOI: 10.1002/mas.21765 -
ELife Oct 2023Why do some inhibitors select the on-state in ERK2, a kinase that is involved in many signaling pathways in cells, whereas others bind to more than one conformation?
Why do some inhibitors select the on-state in ERK2, a kinase that is involved in many signaling pathways in cells, whereas others bind to more than one conformation?
Topics: Phosphorylation; Protein Conformation; Signal Transduction
PubMed: 37850630
DOI: 10.7554/eLife.92753 -
Nature Communications Jun 2024Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks,...
Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks, allowing for the incorporation of deuterium atoms and functional groups into a target molecule in a single step. Unfortunately, the limited availability of synthetic approaches to deuterated synthons has impeded progress in this field. Here, we present an approach utilizing alkyl-substituted thianthrenium salts that efficiently and selectively introduce deuterium at the α position of alkyl chains through a pH-dependent HIE process, using DO as the deuterium source. The resulting α-deuterated alkyl thianthrenium salts, which bear two deuterium atoms, exhibit excellent selectivity and deuterium incorporation in electrophilic substitution reactions. Through in situ formation of isotopically labelled alkyl halides, these thianthrenium salts demonstrate excellent compatibility in a series of metallaphotoredox cross-electrophile coupling with (hetero)aryl, alkenyl, alkyl bromides, and other alkyl thianthrenium salts. Our technique allows for a wide range of substrates, high deuterium incorporation, and precise control over the site of deuterium insertion within a molecule such as the benzyl position, allylic position, or any alkyl chain in between, as well as neighboring heteroatoms. This makes it invaluable for synthesizing various deuterium-labeled compounds, especially those with pharmaceutical significance.
PubMed: 38871683
DOI: 10.1038/s41467-024-48590-w