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1. Radical-disulfide exchange in thiol–ene–disulfidation polymerizations

   https://doi.org/10.1039/d2py00172a  

   Bongiardina, Nicholas J.; Soars, Shafer M.; Podgorski, Maciej; Bowman, Christopher N. (July 2022, Polymer Chemistry)

   Radical-disulfide exchange reactions in thiol–ene–disulfide networks were evaluated for several structurally distinct thiol and disulfide containing monomers. A new dimercaptopropionate disulfide monomer was introduced to assess how different disulfide moieties affect the exchange process and how the dynamic exchange impacts polymerization. The stress relaxation rate for the disulfides studied herein was highly tunable over a narrow range of network compositions, ranging from 50% relaxation over 10 minutes to complete relaxation over a few seconds, by changing the thiol–disulfide stoichiometry or the disulfide type in the monomer. The thiol/disulfide monomer pair was shown to have significant influence on how radical-disulfide exchange impacts the polymerization rate, where pairing a more stable radical forming thiol ( e.g. an alkyl thiol) with a less stable radical-forming disulfide ( e.g. a dithioglycolate disulfide) reduces the rate of the thiol–ene reaction by over an order of magnitude compared to the case where those two radicals are of the same type. The variations in rates of radical-disulfide exchange with dithioglycolate and dimercaptopropionate disulfides had a significant impact on stress relaxation and polymerization stress, where the stress due to polymerization for the final dimercaptopropionate network was about 20% of the stress in the equivalent dithiogylcolate network under the same conditions. These studies provide a fundamental understanding of this polymerization scheme and enable its implementation in materials design. 

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2. Characterization and effect of metal ions on the formation of the Thermus thermophilus Sco mixed disulfide intermediate

   https://doi.org/10.1002/pro.3502  

   Lopez, Liezelle C.; Mukhitov, Nikita; Handley, Lindsey D.; Hamme, Cristina S.; Hofman, Cristina R.; Euers, Lindsay; McKinney, Jennifer R.; Piers, Amani D.; Wadler, Ellen; Hunsicker‐Wang, Laura M. (October 2018, Protein Science)

   Abstract The Sco protein fromThermus thermophilushas previously been shown to perform a disulfide bond reduction in the Cu_Aprotein fromT. thermophilus, which is a soluble protein engineered from subunit II of cytochromeba₃oxidase that lacks the transmembrane helix. The native cysteines onTtSco andTtCu_Awere mutated to serine residues to probe the reactivities of the individual cysteines. Conjugation of TNB to the remaining cysteine inTtCu_Aand subsequent release upon incubation with the complementaryTtSco protein demonstrated the formation of the mixed disulfide intermediate. The cysteine ofTtSco that attacks the disulfide bond in the targetTtCu_Aprotein was determined to beTtSco Cysteine 49. This cysteine is likely more reactive than Cysteine 53 due to a higher degree of solvent exposure. Removal of the metal binding histidine, His 139, does not change MDI formation. However, altering the arginine adjacent to the reactive cysteine in Sco (Arginine 48) does alter the formation of the MDI. Binding of Cu²⁺or Cu⁺toTtSco prior to reaction withTtCu_Awas found to preclude formation of the mixed disulfide intermediate. These results shed light on a mechanism of disulfide bond reduction by theTtSco protein and may point to a possible role of metal binding in regulating the activity. ImportanceThe function of Sco is at the center of many studies. The disulfide bond reduction in Cu_Aby Sco is investigated herein and the effect of metal ions on the ability to reduce and form a mixed disulfide intermediate are also probed. 

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3. Cryogenic Electron Microscopy Informed Molecular Dynamics Simulations to Investigate the Disulfide Hydrogel Self‐Assembly

   https://doi.org/10.1002/cphc.202401085  

   Song, Yuanming; Li, Zhaoxu; Mulvey, Justin T; Freites, J Alfredo; Patterson, Joseph P; Tobias, Douglas J (May 2025, ChemPhysChem)

   Disulfide hydrogels, derived from cysteine‐based redox systems, exhibit active self‐assembly properties driven by reversible disulfide bond formation, making them a versatile platform for dynamic material design. Detailed cryogenic electron microscopy (cryo‐EM) analysis reveals a consistent fiber diameter of 5.4 nm for individual fibers. Using cryo‐EM‐informed radial positional restraints, all‐atom molecular dynamics (MD) simulations are employed to reproduce fibers with dimensions closely matching experimental observations, validated further through simulated cryo‐EM images. The MD simulations reveal that the disulfide gelator (CSSC) predominantly adopts an open conformation, with hydrogen bonds emerging as the key intermolecular force stabilizing the fibers. Notably, intermolecular interactions are found to be higher at 70% conversion to the disulfide gelator compared with 100%, comparable with past unrestrained simulations. Water molecules and solute‐water hydrogen bonds are present throughout the fiber, indicating that the fiber remains hydrated. These findings underscore the potential role of the thiol precursor CSH in stabilizing the transient phase and highlight the importance of CSH‐CSSC interplay. Herein, it provides novel insights into molecular mechanisms governing active self‐assembly and offers strategies for designing tunable materials through controlled assembly conditions. 

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4. Lipoic acid-based poly(disulfide)s: Synthesis and biomedical applications

   https://doi.org/10.1016/j.ntm.2023.100006  

   Levkovskyi, Ivan O.; Mochizuki, Shota; Zheng, Ajay; Zhang, Xiao; Zhang, Fuwu (September 2023, Nano TransMed)

   Ye, Qingsong (Ed.)

   Biodegradable and adaptable polymeric materials are currently being studied due to their wide scope of potential applications, from nanomedicine to novel multifunctional materials. One such class of polymers are poly(disulfide)s, which contain repeating disulfide bonds in their main chain. Lipoic acid, or thioctic acid, is a biologically derived small molecule containing a 1,2-dithiolane ring capable of undergoing ring opening polymerization to yield poly(disulfide)s. In this review, we highlight the synthesis of lipoic acid-based poly(disulfide)s through thermal and thiolate-initiated ring opening polymerizations, and the development of methodology pertaining to the synthetic methods. We further discuss the biomedical applications of poly(disulfide)s, which have been widely used to construct various responsive biomaterials, including polymer-drug conjugates, nanoparticles, hydrogels, and adhesives. 

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5. Chickpea NCR13 disulfide cross-linking variants exhibit profound differences in antifungal activity and modes of action

   https://doi.org/10.1371/journal.ppat.1012745  

   Godwin, James; Djami-Tchatchou, Arnaud Thierry; Velivelli, Siva_L S; Tetorya, Meenakshi; Kalunke, Raviraj; Pokhrel, Ambika; Zhou, Mowei; Buchko, Garry W; Czymmek, Kirk J; Shah, Dilip M (December 2024, PLOS Pathogens)

   Dinesh-Kumar, Savithramma P (Ed.)

   Small cysteine-rich antifungal peptides with multi-site modes of action (MoA) have potential for development as biofungicides. In particular, legumes of the inverted repeat-lacking clade express a large family of nodule-specific cysteine-rich (NCR) peptides that orchestrate differentiation of nitrogen-fixing bacteria into bacteroids. These NCRs can form two or three intramolecular disulfide bonds and a subset of these peptides with high cationicity exhibits antifungal activity. However, the importance of intramolecular disulfide pairing and MoA against fungal pathogens for most of these plant peptides remains to be elucidated. Our study focused on a highly cationic chickpea NCR13, which has a net charge of +8 and contains six cysteines capable of forming three disulfide bonds. NCR13 expression inPichia pastorisresulted in formation of two peptide folding variants, NCR13_PFV1 and NCR13_PFV2, that differed in the pairing of two out of three disulfide bonds despite having an identical amino acid sequence. The NMR structure of each PFV revealed a unique three-dimensional fold with the PFV1 structure being more compact but less dynamic. Surprisingly, PFV1 and PFV2 differed profoundly in the potency of antifungal activity against several fungal plant pathogens and their multi-faceted MoA. PFV1 showed significantly faster fungal cell-permeabilizing and cell entry capabilities as well as greater stability once inside the fungal cells. Additionally, PFV1 was more effective in binding fungal ribosomal RNA and inhibiting protein translationin vitro. Furthermore, when sprayed on pepper and tomato plants, PFV1 was more effective in reducing disease symptoms caused byBotrytis cinerea, causal agent of gray mold disease in fruits, vegetables, and flowers. In conclusion, our work highlights the significant impact of disulfide pairing on the antifungal activity and MoA of NCR13 and provides a structural framework for design of novel, potent antifungal peptides for agricultural use. 

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