Alleviating cellular oxidative stress through treatment with superoxide-triggered persulfide prodrugs.

Overproduction of superoxide anion (O 2 ∙ - ), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O 2 ∙ - to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H 2 S). Termed SOPD-NAC , this persulfide donor reacts specifically with O 2 ∙ - , decomposing to generate N -acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self-assembling peptide (Bz-CFFE-NH 2 ) to make a superoxide-responsive, persulfide-donating peptide ( SOPD-Pep ). Both SOPD-NAC and SOPD-Pep delivered persulfides/H 2 S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than SOPD-NAC and several control compounds, including common H 2 S donors.

• Publication year

  2020

• Venue

  Angewandte Chemie

• Publication date

  2020-06-26

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1002/anie.202006656PMID 32592216PMCID PMC7719095
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A reactive oxygen species (ROS) activated hydrogen sulfide (H2S) donor with self-reporting fluorescence.

  2020cited by this paper
• Polymeric persulfide prodrugs: Mitigating oxidative stress through controlled delivery of reactive sulfur species.

  2020cited by this paper
• Supramolecular nanostructures with tunable donor loading for controlled H2S release.

  2019cited by this paper
• Enhanced cellular uptake and nuclear accumulation of drug-peptide nanomedicines prepared by enzyme-instructed self-assembly.

  2019cited by this paper
• One- and Two-Photon Activated Cysteine Persulfide Donors for Biological Targeting.

  2019cited by this paper
• Reactive oxygen species-triggered off-on fluorescence donor for imaging hydrogen sulfide delivery in living cells

  2019cited by this paper
• Hydrogen sulfide: a gaseous signaling molecule modulates tissue homeostasis: implications in ophthalmic diseases

  2019cited by this paper
• Hydrogen Sulfide-releasing peptide hydrogel limits the development of intimal hyperplasia in human vein segments.

  2019cited by this paper
• Supramolecular Tuning of H2S Release from Aromatic Peptide Amphiphile Gels: Effect of Core Unit Substituents.

  2019cited by this paper
• Reactive Oxygen Species-Triggered Tunable Hydrogen Sulfide Release.

  2018cited by this paper
• Tandem Molecular Self-Assembly in Liver Cancer Cells.

  2018cited by this paper
• Fabricating PLGA microparticles with high loads of the small molecule antioxidant N‐acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress

  2018cited by this paper
• A Vinyl-Boronate Ester-Based Persulfide Donor Controllable by Hydrogen Peroxide, a Reactive Oxygen Species (ROS).

  2018cited by this paper
• A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential.

  2018cited by this paper
• Self-Assembled Nanostructures Regulate H2S Release from Constitutionally Isomeric Peptides

  2018cited by this paper
• Esterase-Sensitive Glutathione Persulfide Donor.

  2018cited by this paper
• N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production.

  2018cited by this paper
• A two-channel responsive fluorescent probe with AIE characteristics and its application for selective imaging of superoxide anions in living cells.

  2017cited by this paper
• The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine

  2017cited by this paper
• Biological chemistry of hydrogen sulfide and persulfides.

  2017cited by this paper
• An Esterase-Sensitive Prodrug Approach for Controllable Delivery of Persulfide Species.

  2017cited by this paper
• Chemical Biology of H2S Signaling through Persulfidation.

  2017cited by this paper
• Kinetic Insights into Hydrogen Sulfide Delivery from Caged-Carbonyl Sulfide Isomeric Donor Platforms.

  2017cited by this paper
• A phosphinate-based near-infrared fluorescence probe for imaging the superoxide radical anion in vitro and in vivo.

  2016cited by this paper
• Mitochondria-Targeted Fluorescent Probe for Imaging Hydrogen Peroxide in Living Cells.

  2016cited by this paper
• Redox Signaling Regulated by Cysteine Persulfide and Protein Polysulfidation

  2016cited by this paper
• Electrostatic-Driven Lamination and Untwisting of β-Sheet Assemblies.

  2016cited by this paper
• Cellular Internalization of Therapeutic Oligonucleotides by Peptide Amphiphile Nanofibers and Nanospheres.

  2016cited by this paper
• Hydrogen Sulfide Donors Activated by Reactive Oxygen Species.

  2016cited by this paper
• Peptide-based hydrogen sulphide-releasing gels.

  2015cited by this paper
• Design of nanostructures based on aromatic peptide amphiphiles.

  2014cited by this paper
• Fluorescent probes based on nucleophilic substitution-cyclization for hydrogen sulfide detection and bioimaging.

  2014cited by this paper
• ROS function in redox signaling and oxidative stress.

  2014cited by this paper
• Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling

  2014cited by this paper
• Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

  2014cited by this paper
• Discovery of Small-Molecule Enhancers of Reactive Oxygen Species That are Nontoxic or Cause Genotype-Selective Cell Death

  2013cited by this paper
• Self-assembling multidomain peptide fibers with aromatic cores.

  2013cited by this paper
• Physiological implications of hydrogen sulfide: a whiff exploration that blossomed.

  2012cited by this paper
• Self-assembling peptide scaffolds for regenerative medicine.

  2012cited by this paper
• Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137): New Insights Into the Biology of Hydrogen Sulfide

  2008cited by this paper
• Nitric oxide and peroxynitrite in health and disease.

  2007cited by this paper
• Peroxynitrite: biochemistry, pathophysiology and development of therapeutics

  2007cited by this paper
• Hydrogen sulfide-releasing anti-inflammatory drugs.

  2007cited by this paper
• Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice.

  2006cited by this paper
• Selective fluorescent imaging of superoxide in vivo using ethidium-based probes

  2006cited by this paper
• Casting Metal Nanowires Within Discrete Self-Assembled Peptide Nanotubes

  2003cited by this paper
• Molecular mechanisms of N-acetylcysteine actions

  2003cited by this paper
• Reactive oxygen species: oxidative damage and pathogenesis

  1999cited by this paper
• Superoxide Anion Radical (O·̄2), Superoxide Dismutases, and Related Matters*

  1997cited by this paper
• Evidence for formation of diphenylphosphinic peroxy radical intermediate: Spin trapping and chemical reactivity of the new phosphorus radical generated from diphenylphosphinic chloride and superoxide

  1990cited by this paper

• Superoxide-responsive mitochondria-targeting peptide-persulfide donor conjugate for retinal ganglion cells protection in glaucoma.

  2026cites this paper
• A superoxide anion-responsive persulfide prodrug for remedying dry eye disease.

  2026cites this paper
• A superoxide anion-responsive supramolecular polymer from peptide-H2S donor conjugates for preventing liver ischemia-reperfusion injury.

  2026cites this paper
• Curcumin driven formation of self-cascade nanoclusters from urate oxidase-H2S donor conjugates for acute gouty arthritis alleviation.

  2026cites this paper
• A Near-Infrared Fluorescent Probe for Dynamic Monitoring of Superoxide Anions for Early Diagnosis of Cuproptosis-Mediated Acute Kidney Injury.

  2025cites this paper
• Electrospun Polymer Fiber Mats for Persulfide Prodrug Delivery

  2025cites this paper
• Dual role of hydrogen sulfide in the tumor microenvironment of prostate cancer (Review).

  2025cites this paper
• An esterase-sensitive persulfide/hydrogen sulfide generating fluorogenic probe enhances antioxidant response.

  2025cites this paper
• Serendipitous Discovery of Photolytic Thiosulfoxide Formation: Application for Visible-Light-Inducible Manipulation of Supersulfide Level in Biological Systems

  2025cites this paper
• Superoxide anion-responsive persulfide and all-trans retinoic acid co-donating peptide assemblies attenuate myocardial ischemia-reperfusion injury.

  2025cites this paper
• Sulforaphane: An emerging star in neuroprotection and neurological disease prevention.

  2025cites this paper
• Colon-Targeting Supersulfide Donor–Drug Conjugates Align Forces against Inflammation

  2025cites this paper
• Crosstalk-free dual-channel visualization and accurate assessment of acute lung injury using a two-photon fluorescent probe.

  2025cites this paper
• Engineering a Hydrogen Peroxide-Activated Hydrogen Sulfide Donor-Based Fluorescent Agent for Integrated Diagnosis and Therapy of Chronic Wounds.

  2025cites this paper
• Hydrogen sulfide regulation in redox homeostasis and programmed cell death: mechanistic insights and implications in cancer.

  2025cites this paper
• Metabolomic signatures reveal mechanisms of rumen-protected glutathione in mitigating oxidative stress and regulating inflammatory networks in transition dairy cows

  2025cites this paper
• Transpersulfidation or H2S Release? Understanding the Landscape of Persulfide Chemical Biology.

  2024cites this paper
• Transition-Metal-Free Disulfuration of Amides with Trisulfide Dioxides via Formation of Unaccessible S-S-N Bonds.

  2024cites this paper
• Peptide‐Based Supramolecular Therapeutics for Fighting Major Diseases

  2024cites this paper
• Thiiranes: Intelligent Molecules for S-Persulfidation.

  2024cites this paper
• In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress

  2024cites this paper
• Aggregation-Enabled Electrochemistry in Confined Nanopore Capable of Complementary Faradaic and Non-Faradaic Detection.

  2024cites this paper
• Cysteine-rich zinc finger proteins and the nuclear factor kappa-B pathway

  2024cites this paper
• Regulating H2S release from self-assembled peptide H2S-donor conjugates using cysteine derivatives

  2024cites this paper
• A dual channel superoxide anion probe for the rapid visualization of scrap leather-induced neuroinflammation using an intramolecular electron transfer-integrated near-infrared platform.

  2024cites this paper
• Constitutionally Isomeric Peptides: Subtle Changes Leading to Dramatic Differences in Properties

  2024cites this paper
• Prothioconazole exposure disrupts oocyte maturation and fertilization by inducing mitochondrial dysfunction and apoptosis in mice.

  2024cites this paper
• An esterase-cleavable persulfide donor with no electrophilic byproducts and a fluorescence reporter.

  2024cites this paper
• Endogenous chemicals guard health through inhibiting ferroptotic cell death

  2023cites this paper
• Visible-light-induced synthesis of N-disulfanyl indoles, pyrroles or carbazoles via the construction of stable S-S-N bonds.

  2023cites this paper
• Stimulus-Responsive Zwitterionic Prodrug Delivery System with Sustained Release of Hydrogen Sulfide for Protective Aortic Dissection.

  2023cites this paper
• Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

  2023cites this paper
• A tunable fluorescent probe for superoxide anion detection during inflammation caused by Treponema pallidum.

  2023cites this paper
• Hydrogels for Gasotransmitter Delivery: Nitric oxide, carbon monoxide, and hydrogen sulfide.

  2023cites this paper
• Novel Near-Infrared Fluorescence Probe for Bioimaging and Evaluating Superoxide Anion Fluctuations in Ferroptosis-Mediated Epilepsy.

  2023cites this paper
• Mackinawite nanozymes as reactive oxygen species scavengers for acute kidney injury alleviation

  2023cites this paper
• Facile Strategy to Output Fluorescein from Nucleic Acid Interactions.

  2023cites this paper
• Construction of β-Acetoxy or β-Hydroxyl Disulfides via Highly Regioselective Ring-Opening of Epoxides with Acetyl Masked Disulfide Nucleophiles.

  2023cites this paper
• Progress and perspective on hydrogen sulfide donors and their biomedical applications

  2022cites this paper
• Reactive Sulfur Compounds in the Fight against COVID-19

  2022cites this paper
• Nanoceria for ocular diseases: Recent advances and future prospects

  2022cites this paper
• Supramolecular nanomedicines through rational design of self-assembling prodrugs.

  2022cites this paper
• Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs.

  2022cites this paper
• Peptide-based supramolecular photodynamic therapy systems: From rational molecular design to effective cancer treatment

  2022cites this paper
• Enhancing cellular sulfane sulfur through β-glycosidase-activated persulfide donors: mechanistic insights and oxidative stress mitigation.

  2022cites this paper
• Esterase-Activated Perthiocarbonate Persulfide Donors Provide Insights into Persulfide Persistence and Stability.

  2022cites this paper
• Reactive sulfur species and their significance in health and disease

  2022cites this paper
• Photothermally Activated Coacervate Model Protocells as Signal Transducers Endow Mammalian Cells with Light Sensitivity

  2021cites this paper
• The Biological/Physiological Utility of Hydropersulfides (RSSH) and Related Species: What Is Old Is New Again

  2021cites this paper
• A Review of Chemical Tools for Studying Small Molecule Persulfides: Detection and Delivery.

  2021cites this paper
• A mitochondrial and lysosomal targeted ratiometric probe for detecting intracellular H2S.

  2021cites this paper
• Ginsenoside Rd: A promising natural neuroprotective agent.

  2021cites this paper
• Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation

  2021cites this paper
• Methods in sulfide and persulfide research.

  2021cites this paper
• In situ oxidation-regulated self-assembly of peptides into transformable scaffolds for cascade therapy

  2021cites this paper
• Development of Hydropersulfide Donors to Study Their Chemical Biology

  2021cites this paper
• Alkylsulfenyl thiocarbonates: precursors to hydropersulfides potently attenuate oxidative stress†

  2021cites this paper
• Versatile Gold-Coupled Te-Carbon Dots for Quantitative Monitoring and Efficient Scavenging of Superoxide Anions.

  2021cites this paper