-
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 -
Folia Microbiologica Sep 2019The rare stable isotope of hydrogen, deuterium, has fascinated researchers since its discovery in the 1930s. Subsequent large-scale production of deuterium oxide,... (Review)
Review
The rare stable isotope of hydrogen, deuterium, has fascinated researchers since its discovery in the 1930s. Subsequent large-scale production of deuterium oxide, commonly known as heavy water, became a starting point for further research. Deuterium exhibits unique physicochemical properties as well as having the strongest kinetic isotope effects among all other elements. Moreover, a broad variety of morphological and physiological changes have been observed in deuterium-treated cells and organisms, including changes in fundamental processes such as cell division or energy metabolism. Even though our understanding of such alterations is still insufficient, it is evident that some of them make growth in a deuterium-enriched environment a challenging task. There seems to be certain species-specific limits to their tolerance to heavy water, where some organisms are unable to grow in heavy water whilst others have no difficulties. Although the effects of deuterium on living organisms are, in general, negative, some of its applications are of great biotechnological potential, as is the case of stable isotope-labelled compounds or deuterated drugs.
Topics: Animals; Deuterium; Humans; Kinetics; Water
PubMed: 31352668
DOI: 10.1007/s12223-019-00740-0 -
Journal of Medicinal Chemistry Jun 2019The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration... (Review)
Review
The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.
Topics: Animals; Chemistry, Pharmaceutical; Deuterium; Humans
PubMed: 30640460
DOI: 10.1021/acs.jmedchem.8b01808 -
Angewandte Chemie (International Ed. in... Feb 2018Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct... (Review)
Review
Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.
Topics: Deuterium; Enzymes; Isotope Labeling; Kinetics; Metabolomics; Pharmaceutical Preparations; Proteomics; Tritium
PubMed: 28815899
DOI: 10.1002/anie.201704146 -
Chemico-biological Interactions Feb 1999The topic of deuterium isotope effects is usually concerned with the effects on chemical reactions that are caused by the substitution of deuterium atoms for protium, or... (Review)
Review
The topic of deuterium isotope effects is usually concerned with the effects on chemical reactions that are caused by the substitution of deuterium atoms for protium, or hydrogen, atoms in a molecule. These effects include changes in the rate of cleavage of covalent bonds to deuterium, or to an atom located adjacent to deuterium, in a reactant molecule. Deuterium isotope effects on other, noncovalent, interactions between molecules are known to occur, but they are generally considered to be insignificant, especially in biological experiments where deuterium substituted molecules are used as tracers. Noncovalent interactions between molecules include hydrogen bonding, and ionic and van der Waals interactions. This article reviews evidence for deuterium isotope effects on noncovalent interactions, with an emphasis on binding interactions between molecules of biological interest, but also including examples of nonbiological molecules in order to demonstrate the generality of these effects. The reality of this effect relies on the assumption that the only difference between the isotopomers considered is the presence of deuterium or hydrogen; there are no impurities present. The physical basis of the effect may be due to differences in the polarities and/or sizes of deuterated versus nondeuterated isomers, and the extent of a deuterium isotope effect on a noncovalent interaction depends on the site of deuteration within a biomolecule. The presence of this effect requires careful interpretation of results obtained in experiments with deuterium labeled compounds.
Topics: Animals; Binding Sites; Deuterium; Humans; Hydrogen Bonding; Isotope Labeling; Molecular Structure
PubMed: 10190576
DOI: 10.1016/s0009-2797(98)00097-0 -
Carbohydrate Research Aug 2023Carbohydrates and glycans are integral to many biological processes, including cell-cell recognition and energy storage. However, carbohydrates are often difficult to...
Carbohydrates and glycans are integral to many biological processes, including cell-cell recognition and energy storage. However, carbohydrates are often difficult to analyze due to the high degree of isomerism present. One method being developed to distinguish these isomeric species is hydrogen/deuterium exchange-mass spectrometry (HDX-MS). In HDX-MS, carbohydrates are exposed to a deuterated reagent and the functional groups with labile hydrogen atoms, including hydroxyls and amides, exchange with the 1 amu heavier isotope, deuterium. These labels can then be detected by MS, which monitors the mass increase with the addition of D-labels. The observed rate of exchange is dependent on the exchanging functional group, the accessibility of the exchanging functional group, and the presence of hydrogen bonds. Herein, we discuss how HDX has been applied in the solution-phase, gas-phase, and during MS ionization to label carbohydrates and glycans. Additionally, we compare differences in the conformations that are labeled, the labeling timeframes, and applications of each of these methods. Finally, we comment on future opportunities for development and use of HDX-MS to analyze glycans and glycoconjugates.
Topics: Hydrogen; Deuterium; Carbohydrates; Amides; Hexoses
PubMed: 37290371
DOI: 10.1016/j.carres.2023.108859 -
Journal of the American Society For... Apr 2022This note describes theoretical and experimental considerations to observe perturbation of a protein upon binding to a ligand with weak affinity by hydrogen/deuterium...
This note describes theoretical and experimental considerations to observe perturbation of a protein upon binding to a ligand with weak affinity by hydrogen/deuterium exchange mass spectrometry (HDX-MS). The most popular application of HDX-MS is to determine the binding site of a drug or drug lead in a protein target. However, when the affinity of a ligand is weak, driving the equilibrium to the formation of a complex is difficult, and thus, observing the perturbation upon binding is also challenging. Theoretical consideration indicates that the original concentration of a ligand over the dissociation constant ([L]/) is roughly equal to the maximum protection factor expected for the experiment when the original concentration of a ligand is significantly larger than the original concentration of a protein and the dissociation constant ([L] ≫ [P] and [L] ≫ ). When HDX-MS analysis of a protein with a ligand of low affinity and low solubility is carried out, it may be challenging to achieve high enough ligand concentration to drive the equilibrium in favor of the complex due to the low solubility. There are two methods to alleviate this issue: (i) spiking a low affinity/low solubility ligand to exchange buffer to lower the required ligand concentration in aqueous protein stock solution and (ii) mixing a 1:1 ratio of aqueous protein-ligand stock solution and deuterated buffer to initiate the exchange reaction instead of the commonly used 1:9 ratio.
Topics: Deuterium; Deuterium Exchange Measurement; Hydrogen Deuterium Exchange-Mass Spectrometry; Mass Spectrometry; Proteins
PubMed: 35230104
DOI: 10.1021/jasms.1c00375 -
Analytica Chimica Acta Oct 2016Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical... (Review)
Review
Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways. In manufacturing and development, HDX-MS can validate storage formulations and manufacturing processes for various biotherapeutics. Currently, HDX-MS is being refined to provide additional coverage, sensitivity and structural specificity and implemented on the millisecond timescale to reveal residual structure and dynamics in disordered domains and intrinsically disordered proteins.
Topics: Biopharmaceutics; Deuterium; Drug Discovery; Hydrogen; Mass Spectrometry
PubMed: 27662755
DOI: 10.1016/j.aca.2016.08.006 -
Die Pharmazie Sep 2022H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl...
H/D exchange reactions can be observed by NMR spectroscopy of acebutolol (ACE). The results obtained showed deuterium incorporation at α-posi t ion of the carbonyl group of acebutolol, when using deuterium oxide or deuterated methanol as deuterium source and solvent. The spontaneous deuteration is proceeded by the following pathway CH₃→CH₂D→CHD→CD₃, through a keto-enol tautomerization reaction. Furthermore, LC-MS / QTOF analyses have confirmed the proposed H/D exchange. In order to reduce the time of total deuteration observed at the acetyl group alkaline catalysts were employed.
Topics: Acebutolol; Deuterium; Deuterium Oxide; Hydrogen; Methanol; Solvents
PubMed: 36199187
DOI: 10.1691/ph.2022.2419 -
Progress in Nuclear Magnetic Resonance... Feb 2014A description of the utility of deuteration in protein NMR is provided with an emphasis on quantitative evaluation of the effects of deuteration on a number of NMR... (Review)
Review
A description of the utility of deuteration in protein NMR is provided with an emphasis on quantitative evaluation of the effects of deuteration on a number of NMR parameters of proteins: (1) chemical shifts, (2) scalar coupling constants, (3) relaxation properties (R1 and R2 rates) of nuclei directly attached to one or more deuterons as well as protons of methyl groups in a highly deuterated environment, (4) scalar relaxation of 15N and 13C nuclei in 15N-D and 13C-D spin systems as a measure of hydrogen bonding strength, and (5) NOE-based applications of deuteration in NMR studies of protein structure. The discussion is restricted to the 'indirect' use of deuterium in the sense that the description of NMR parameters and properties of the nuclei affected by nearby deuterons (15N, 13C, 1H) is provided rather than those of deuterium itself.
Topics: Deuterium; Hydrogen Bonding; Nuclear Magnetic Resonance, Biomolecular; Proteins; Solutions
PubMed: 24411830
DOI: 10.1016/j.pnmrs.2013.08.001