-
Journal of Medicinal Chemistry Feb 2020The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides...
The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with and IC values of 26 nM and 0.891 μM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53-MDM2/MDMX interaction. Using fluorescence polarization assays, circular dichroism, nuclear magnetic resonance spectroscopy, and computational simulations, we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53-MDM2 interaction by binding to the hydrophobic cleft of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-γ-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.
Topics: Binding Sites; Cell Cycle Proteins; Cell Line, Tumor; Humans; Peptidomimetics; Protein Binding; Protein Conformation, alpha-Helical; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Sulfones; Tumor Suppressor Protein p53
PubMed: 31971801
DOI: 10.1021/acs.jmedchem.9b00993 -
Environmental and Molecular Mutagenesis Jul 2022Bisphenol A (BPA), a recognized endocrine-disrupting chemical, is used in the production of epoxy and polycarbonate resins. Since human exposure to BPA has been...
Bisphenol A (BPA), a recognized endocrine-disrupting chemical, is used in the production of epoxy and polycarbonate resins. Since human exposure to BPA has been associated with increased cancer susceptibility, the market has shifted to products often labeled as "BPA free" containing BPA analogs such as bisphenol F (BPF) and bisphenol S (BPS). However, the European legislation on BPF and BPS is still unclear. This study analyzed the effects of BPA, BPF, and BPS exposure on human peripheral blood mononuclear cells by using in vitro micronucleus assay. Furthermore, it investigated the impact of bisphenols exposure on human endogenous retroviruses (HERVs) expression, which is implicated with the pathogenesis of several human diseases. The micronucleus assay revealed a significant genotoxic effect in peripheral blood cells after exposure to BPA and BPF at concentrations of 0.1, 0.05, and 0.025 μg/ml, and to BPS at 0.1 and 0.05 μg/ml. In addition, BPA exposure seems to upregulate the expression of HERVs, while a downregulation was observed after BPF and BPS treatments. Overall, our data showed the toxic effect of BPA and its analogs on circulating cells in the blood and demonstrated that they could modulate the HERVs expression.
Topics: Benzhydryl Compounds; Endogenous Retroviruses; Genomics; Humans; Leukocytes, Mononuclear; Phenols; Sulfones
PubMed: 36054626
DOI: 10.1002/em.22499 -
Bone Marrow Transplantation Jul 2023Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT)....
Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at -52 or -69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at -52 (rs3957356) and -69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.
Topics: Adult; Humans; Busulfan; Pharmacogenetics; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Polymorphism, Genetic; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37085674
DOI: 10.1038/s41409-023-01963-z -
Molecules (Basel, Switzerland) May 2023Sulfonamides are one of the oldest groups of veterinary chemotherapeutic agents. Physico-chemical properties, the concentration and the nature of the environment are the...
Sulfonamides are one of the oldest groups of veterinary chemotherapeutic agents. Physico-chemical properties, the concentration and the nature of the environment are the factors responsible for the distribution of sulfonamides in the living organism. Although these drug compounds have been in use for more than half a century, knowledge about their behavior is still limited. Physiological activity is currently attributed to the sulfanyl radical. Our study is devoted to the spectral properties of aqueous solutions of sulfaguanidine, in which the formation of complexes with an H-bond and a protonated form takes place. The nature of the fluorescent state of sulfaguanidine was interpreted using computational chemistry, the electronic absorption method and the luminescence method. The structure of sulfaguanidine includes several active fragments: aniline, sulfonic and guanidine. To reveal the role of fragments in the physiological activity of the studied antibiotic, we calculated and compared the effective charges of the fragments of aniline and sulfaguanidine molecules. Chromophore groups were identified in molecules, which determine the intermolecular interaction between a molecule and a proton-donor solvent. The study also revealed the impact of sulfone and guanidine groups, as well as complexation, on the effective charge of the antibiotic fragment responsible for physiological activity and luminescent ability.
Topics: Sulfaguanidine; Luminescence; Anti-Bacterial Agents; Sulfonamides; Sulfanilamide; Aniline Compounds; Guanidines
PubMed: 37241901
DOI: 10.3390/molecules28104159 -
Nature Communications Sep 2020Natural biomolecules such as peptides and DNA can dynamically self-organize into diverse hierarchical structures. Mimicry of this homopolymer self-assembly using...
Natural biomolecules such as peptides and DNA can dynamically self-organize into diverse hierarchical structures. Mimicry of this homopolymer self-assembly using synthetic systems has remained limited but would be advantageous for the design of adaptive bio/nanomaterials. Here, we report both experiments and simulations on the dynamic network self-assembly and subsequent collapse of the synthetic homopolymer poly(propylene sulfone). The assembly is directed by dynamic noncovalent sulfone-sulfone bonds that are susceptible to solvent polarity. The hydration history, specified by the stepwise increase in water ratio within lower polarity water-miscible solvents like dimethylsulfoxide, controls the homopolymer assembly into crystalline frameworks or uniform nanostructured hydrogels of spherical, vesicular, or cylindrical morphologies. These electrostatic hydrogels have a high affinity for a wide range of organic solutes, achieving >95% encapsulation efficiency for hydrophilic small molecules and biologics. This system validates sulfone-sulfone bonding for dynamic self-assembly, presenting a robust platform for controllable gelation, nanofabrication, and molecular encapsulation.
Topics: Alkenes; Hydrogels; Hydrophobic and Hydrophilic Interactions; Polypropylenes; Static Electricity; Sulfones
PubMed: 32994414
DOI: 10.1038/s41467-020-18657-5 -
Proceedings of the National Academy of... Sep 2019Dimethylsulfide (DMS), a gas produced by marine microbial food webs, promotes aerosol formation in pristine atmospheres, altering cloud radiative forcing and...
Dimethylsulfide (DMS), a gas produced by marine microbial food webs, promotes aerosol formation in pristine atmospheres, altering cloud radiative forcing and precipitation. Recent studies suggest that DMS controls aerosol formation in the summertime Arctic atmosphere and call for an assessment of pan-Arctic DMS emission (EDMS) in a context of dramatic ecosystem changes. Using a remote sensing algorithm, we show that summertime EDMS from ice-free waters increased at a mean rate of 13.3 ± 6.7 Gg S decade (∼33% decade) north of 70°N between 1998 and 2016. This trend, mostly explained by the reduction in sea-ice extent, is consistent with independent atmospheric measurements showing an increasing trend of methane sulfonic acid, a DMS oxidation product. Extrapolation to an ice-free Arctic summer could imply a 2.4-fold (±1.2) increase in EDMS compared to present emission. However, unexpected regime shifts in Arctic geo- and ecosystems could result in future EDMS departure from the predicted range. Superimposed on the positive trend, EDMS shows substantial interannual changes and nonmonotonic multiyear trends, reflecting the interplay between physical forcing, ice retreat patterns, and phytoplankton productivity. Our results provide key constraints to determine whether increasing marine sulfur emissions, and resulting aerosol-cloud interactions, will moderate or accelerate Arctic warming in the context of sea-ice retreat and increasing low-level cloud cover.
Topics: Aerosols; Arctic Regions; Atmosphere; Climate; Ecosystem; Ice Cover; Mesylates; Oceans and Seas; Phytoplankton; Seasons; Seawater; Sulfides
PubMed: 31501321
DOI: 10.1073/pnas.1904378116 -
Environment International Jan 2024Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP,... (Comparative Study)
Comparative Study
Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP, remains poorly understood. Multi-omics approaches were used in this study to determine the effects of foodborne and airborne PES MNP on liver and lung, respectively. Foodborne MNP were capable of inducing gut microbial dysbiosis, gut and serum metabolic disruption, and liver transcriptomic dysregulation, and affecting serum antioxidant activity and liver function, resulting in liver injury. As for the airborne MNP, they were found to induce nasal and lung microbial dysbiosis, serum and lung metabolic disruption, and liver transcriptome disturbance, and cause disrupted serum antioxidant activity and lung injury. Foodborne and airborne PES NP were found to respectively induce greater liver and lung toxicity than MP, which could be associated with the differences between NP and MP exposures. The relevant results suggest that foodborne PES MNP could disrupt the "gut microbiota-gut-liver" axis and induce hepatic injury, while airborne PES MNP could affect the "airborne microbiota-lung" axis and cause lung injury. The findings could benefit the diagnoses of liver and lung injury respectively induced by foodborne and airborne PES MNP, as well as the proper use of PES in human living environment.
Topics: Animals; Humans; Mice; Antioxidants; Dysbiosis; Liver; Lung Injury; Microplastics; Plastics; Polymers; Sulfones
PubMed: 38043322
DOI: 10.1016/j.envint.2023.108350 -
IUCrData Oct 2021The title mol-ecular salt, CHNOS·CHOS, consists of a cationic sulfonated pyridine -oxide moiety and a methane-sulfonate anion. An N-O bond length of 1.4004 (15) Å...
The title mol-ecular salt, CHNOS·CHOS, consists of a cationic sulfonated pyridine -oxide moiety and a methane-sulfonate anion. An N-O bond length of 1.4004 (15) Å is observed in the cation. In the crystal, weak C-H⋯O inter-actions link the components into a three-dimensional network.
PubMed: 36340987
DOI: 10.1107/S2414314621010269 -
Environmental Research Mar 2022The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union,... (Review)
Review
The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 μg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies.
Topics: Animals; Benzhydryl Compounds; Biological Availability; Endocrine Disruptors; Female; Humans; Male; Phenols; Reference Values; Sulfones; Swine
PubMed: 34688643
DOI: 10.1016/j.envres.2021.112233 -
Hypertension Research : Official... Apr 2021The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with... (Review)
Review
The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I-III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.
Topics: Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Pyrroles; Sulfones
PubMed: 33214722
DOI: 10.1038/s41440-020-00569-y