Peptide Bond Research Articles

Discovery of Cyclic Peptide Inhibitors Targeted on TNFα-TNFR1 from Computational Design and Bioactivity Verification.

Activating tumor necrosis factor receptor 1 (TNFR1) with tumor necrosis factor alpha (TNFα) is one of the key pathological mechanisms resulting in the exacerbation of rheumatoid arthritis (RA) immune response. Despite various types of drugs being available for the treatment of RA, a series of shortcomings still limits their application. Therefore, developing novel peptide drugs that target TNFα-TNFR1 interaction is expected to expand therapeutic drug options. In this study, the detailed interaction mechanism between TNFα and TNFR1 was elucidated, based on which, a series of linear peptides were initially designed. To overcome its large conformational flexibility, two different head-to-tail cyclization strategies were adopted by adding a proline-glycine (GP) or cysteine-cysteine (CC) to form an amide or disulfide bond between the N-C terminal. The results indicate that two cyclic peptides, R1_CC4 and α_CC8, exhibit the strongest binding free energies. α_CC8 was selected for further optimization using virtual mutations through in vitro activity and toxicity experiments due to its optimal biological activity. The L16R mutant was screened, and its binding affinity to TNFR1 was validated using ELISA assays. This study designed a novel cyclic peptide structure with potential anti-inflammatory properties, possibly bringing an additional choice for the treatment of RA in the future.

Insights into Chemical Bonding Modes and Heat Transport at the Molecular Level.

Despite the demand for nanoscale thermal management technologies of material surfaces and interfaces using organic molecules, heat transport properties at the single molecular level remain elusive due to the experimental difficulty of measuring temperature at the nanoscopic scale. Here we show how chemical bonding modes can affect the heat transport properties of single molecules. We focused on four molecular systems: benzylthiol linked to another phenyl group by either a triple (compound 1), double (3), or amide (4) bond and a common linear alkanethiol (2), all of which are nearly identical in molecular length. We prepared binary self-assembled monolayers (SAMs) using 1 as a common reference in combination with 2-4 and investigated their relative heat transport properties using scanning thermal microscopy (SThM). Two-dimensional temperature mapping of the binary SAMs showed that C≡C and C=C bonds provide more effective pathways for heat transport compared to C-C bonds. Since the amide molecule has resonance structures with C=N double bond character, we expected that its heat transport properties would be comparable to those of the thiols containing triple or double bonds. However, the heat transport properties of this molecule prevailed over the others, most likely due to the formation of additional heat transport pathways caused by intermolecular hydrogen bonding. These findings may provide important guidelines for the design of organic materials for nanoscale thermal management.

Dynamic covalent epoxy network of hyperbranched-synergistic-supramolecular: Catalyst-free reprocessing, and application in carbon fiber composites recycling

Plastic recycling, especially the recycling of thermosets, is a crucial step towards improving waste management and achieving economic recycling. Here, a method utilizing non-covalent supramolecular interactions and synergistic hyperbranched structures is reported to endow transesterification-based thermosetting materials with recyclability in the absence of a catalyst. A hyperbranched epoxy resin curing agent (HPCA) containing amide bonds, terminated by amine and ester, was designed and synthesized, and further cured with bisphenol A epoxy resin. The hyperbranched topological structure and its abundant amide bonds contribute to the formation of a dense hydrogen bonding network, enhancing the reprocessability, thermal, and mechanical properties of the material. As a result, the resin can be reprocessed by hot pressing at 190 °C and 10 MPa for 40 min without catalyst. Moreover, amide and ester bonds endow resin materials with excellent degradation performance in alkaline solutions, laying the foundation for the recycling and utilization of carbon fibers in composite materials.

Chemoselective modification of chitosan with arginine and hydroxyproline: Development of antibacterial composite films for wound healing applications

This study explored the enhancement of chitosan for wound dressing applications through selective functionalization with arginine and hydroxyproline amino acids, combined with polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) in composite films. The research employed chemoselective amino acid grafting followed by solution casting to fabricate the composite materials. Fourier transform infrared (FTIR) analysis verified successful chitosan modification through the presence of a carbamate bond at 1719 cm−1 and an amide bond shift from 1660 to 1680 cm−1, with nuclear magnetic resonance (NMR) analysis providing additional confirmation. The composite films demonstrated exceptional properties, achieving maximum tensile strength of approximately 55 MPa and swelling ratio of about 400 %. Statistical analysis revealed significant variations in mechanical and swelling properties across formulations (p < 0.05), with analysis of variance (ANOVA) showing a between-group sum of squares of 122,980.519 for tensile strength and 352,306.333 for swelling. Duncan's multiple range test identified distinct groupings for tensile strength (5.67–119.67 MPa) and swelling ratios (320.33–565.33 %), demonstrating the impact of composition on material properties. Thermal stability analysis (25–600 °C) revealed a multi-step degradation process, confirming successful modification and composite formation. The amino acid-modified chitosan composites showed remarkable antibacterial enhancement, exhibiting 60 % greater activity against both Gram-positive and Gram-negative bacteria compared to unmodified chitosan. These findings demonstrate the potential of selectively functionalized chitosan composite films for advanced wound dressing applications, combining enhanced antibacterial efficacy with robust mechanical and thermal properties. Future research directions include formulation optimization and in vivo validation of clinical efficacy.

Identifying Novel Inhibitors for Dengue NS2B-NS3 Protease by Combining Topological similarity, Molecular Dynamics, MMGBSA and SiteMap Analysis.

DENV NS2B-NS3 protease inhibitors were designed based upon the reference molecule, 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl) benzenesulfonamide, reported by our team with the aim to optimize lead compound via rational approach. Top five best scoring molecules with zinc ids ZINC23504872, ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613 bearing 'pyrimidin-4(3H)-one' basic scaffold have been identified as a promising candidate against DENV protease enzyme. The shape and electrostatic complementary between identified HITs and reference molecules were found to be Tanimotoshape 0.453, 0.690, 0.680, 0.685 & 0.672 respectively and Tanimotoelectrostatic 0.211, 0.211, 0.441, 0.442, 0.442 and 0.442 respectively. The molecular docking studies suggested that the identified HITs displayed the good interactions with active site residues and lower binding energies. The stability of docked complexes was assessed by MD simulations studies. The RMSD values of protein backbone (1.6779, 3.1563, 3.3634, 3.3893 & 3.0960 Å) and protein backbone RMSF values (1.0126, 1.0834, 1.0890, 0.9974 & 1.0080 Å respectively) for all top five HITs were stable and molecules did not fluctuate from the active pocket during entire 100ns MD run. The druggability Dscore below 1 indicate the tightly binding of ligand at the active site. Dscore for ZINC23504872 was found to be 1.084 while for the second class of compounds ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613, 0.503, 0.484, 0.487 and 0.501 Dscores were observed. In-silico ADMET calculations suggested that all five HITs were possessed the drug likeliness properties and did not violate the Lipinski's rule of five. Summing up, these in-silico generated data suggested that the identified molecules bearing pyrimidin-4(3H)-one would be promising scaffold for DENV protease inhibitors. However, experimental results are needed to prove the obtained results.

Dipeptidyl Peptidase-4 Inhibitors: A Systematic Review of Structure-Activity Relationship Studies

Context: Dipeptidyl peptidase 4 (DPP-4) is a serine exopeptidase enzyme that hydrolyzes the amide bond at the N-terminal of peptides. This enzyme converts incretins, such as glucagon-like peptide I and glucose-dependent insulinotropic peptide, into their inactive forms, thereby preventing them from stimulating insulin secretion. Numerous studies have confirmed the role of DPP-4 in the pathophysiology of type 2 diabetes, leading to the development of various DPP-4 inhibitors. In recent years, research on DPP-4 inhibitors has expanded significantly, resulting in the creation of both non-peptidomimetic heterocyclic compounds and peptidomimetic scaffolds. Evidence Acquisition: This systematic review summarizes all recent advances related to DPP-4 inhibitors up to 2024. It begins by outlining the biochemical characteristics of DPP-4 and general pharmacological principles of DPP-4 inhibition, followed by an overview of the latest developments from recent publications. The review provides valuable insights into the pharmacophores necessary for ligand-protein interactions, aimed at understanding the structure-activity relationship of novel DPP-4 inhibitors. Data for this review was collected from sources including ScienceDirect, PubMed, and Scopus. Results: This review highlights various chemical scaffolds that have been explored in the development of novel DPP-4 inhibitors. It emphasizes scaffolds with significant DPP-4 inhibitory activity, including azoles, azines, sulfonamides, and quinolone motifs. The article also details the structure-activity relationships of newly developed analogs, providing a comprehensive overview of recent advancements in this area. Conclusions: Despite moderate progress in the development of novel DPP-4 inhibitors, emerging molecular aspects of DPP-4 intervention show great promise for future therapeutic developments.

Mainchain and sidechain-involving H-bonded asymmetric polyimides containing rigid amide and flexible ether linkages

Hydrogen bonds (H-bonds), usually mainchain amide H-bonds, have been well recognized to play important roles in modulating the properties of polyimides (PIs) by strengthening macromolecular interaction. While the structure-properties relationships of symmetric mainchain amide H-bonded PIs have been extensively researched, the asymmetric H-bonded PIs, particularly those containing rigid-flexible backbone structure, and sidechain-involving H-bonds, have been rarely explored. Herein, starting from designed synthesis of diamine monomers, we present two series of asymmetric PIs containing rigid amide and flexible ether linkages that form mainchain amide-amide and amide-imide H-bonds, lacking or bearing pendent trifluoromethyls (-CF3) that form sidechain-involving amide-CF3 H-bonds. The presence of these three types of H-bonds were revealed by RDF simulation and confirmed by FTIR. Mainchain H-bonded PIs (PI-Ax) show higher Tg than sidechain-involving H-bonded PIs (PI-Tx), while PI-Tx series exhibit higher optical transparency and hydrophobicity, lower dielectric constant (ε′) and better mechanical properties than PI-Ax. The general researches on the PIs’ solubility, WAXD spectra, thermal properties, fluorescence emission and optical transparency, the dihedral angles (φ), fractional free volume (FFV), theoretical gas transport properties, chain geometry optimization and HOMO-LUMO energy gap (ΔE) values have been comprehensively carried out from the aspects of both experiments and theoretical calculation.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N-benzylfuranamide as the model reaction. We demonstrate PestE's potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N-benzylfuranamide by 1.2-fold, and F33L gave a 4-fold increase in conversion to tamibarotene.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N‐benzylfuranamide as the model reaction. We demonstrate PestE’s potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N‐benzylfuranamide by 1.2‐fold, and F33L gave a 4‐fold increase in conversion to tamibarotene.

Strategies to verify equimolar peptide release in mass spectrometry-based protein quantification exemplified for apolipoprotein(a).

Quantitative protein mass spectrometry (MS) is ideally suited for precision diagnostics and for reference standardization of protein analytes. At the Leiden Apolipoprotein Reference Laboratory we apply MS strategies to obtain detailed insight into the protein-to-peptide conversion in order to verify that quantifier peptides are not partly concealed in miscleaved protein backbone. Apolipoprotein(a) (apo(a)) was digested in a non-optimal manner to enhance the number of miscleaved peptides that were identified by high resolution liquid chromatography tandem-MS measurements. The protein-to-peptide conversion was carefully mapped with specific attention for miscleaved peptides that contain an apo(a) quantifier peptide. Four different isotopologues of each apo(a)-quantifier peptide were applied to evaluate linearity of internal peptide standards during measurement of specific real-life samples. Two apo(a) quantifier peptides that were concealed in two different miscleaved peptides were included into a multiple reaction monitoring list in our targeted MS-based apo(a) quantifications to alert for potential protein digestion discrepancies. The presence of miscleaved peptides could be ruled out when applying our candidate reference measurement procedure (RMP) for apo(a) quantification. These data further corroborate the validity of our apo(a) candidate RMP as higher order method for certification of commercial Lp(a) tests that is endorsed by theInternational Federation of Clinical Chemistry and Laboratory Medicine. MS-based molecular detection and quantification of heterogeneous apo(a) proteoforms will allow manufacturers' transitioning from confounded lipoprotein(a) [Lp(a)] mass levels into accurate molar apo(a) levels.

Detouring NSAID into Mitochondria to Induce Apoptosis in Cancer Cells.

In recent years, impairing mitochondria in cancer cells gained attention as alternative cancer therapy. In this context, non-steroidal anti-inflammatory (NSAID) drugs are interesting candidates to damage mitochondria in cancer cells. However, routing NSAIDs specifically into the mitochondria remained a major challenge and less explored. Herein, we have synthesized a small library of Meclofenamic acid and Naproxen derivatives having ester and amide linkage with substituted triphenylphosphonium cations for mitochondria targeting. Screening in cervical cancer (HeLa), breast cancer (MCF7) and colon cancer (HCT-116) cells revealed a Meclofenamic acid derivative having ester linkage with tri (4-methoxyphenyl) phosphonium cation (8A3) which induced mitochondrial damage through mitochondrial outer membrane permeabilization (MOMP) followed by generation of reactive oxygen species (ROS) in the HCT-116 cells. This 8A3-mediated mitochondrial impairment triggered apoptosis by inhibiting Cox-2, reduction in Bcl-2/Bcl-xl expression and Caspase-3/9 cleavage leading to remarkable HCT-116 cell death. This novel mitochondrion targeted Meclofenamic acid derivative has the potential to be used as a chemical biology tool to understand the role of NSAIDs in mitochondria towards cancer therapy.

Scalable protein design using optimization in a relaxed sequence space.

Machine learning (ML)-based design approaches have advanced the field of de novo protein design, with diffusion-based generative methods increasingly dominating protein design pipelines. Here, we report a "hallucination"-based protein design approach that functions in relaxed sequence space, enabling the efficient design of high-quality protein backbones over multiple scales and with broad scope of application without the need for any form of retraining. We experimentally produced and characterized more than 100 proteins. Three high-resolution crystal structures and two cryo-electron microscopy density maps of designed single-chain proteins comprising up to 1000 amino acids validate the accuracy of the method. Our pipeline can also be used to design synthetic protein-protein interactions, as validated experimentally by a set of protein heterodimers. Relaxed sequence optimization offers attractive performance with respect to designability, scope of applicability for different design problems, and scalability across protein sizes.

Structural Plasticity as a Driver of the Maturation of Pro-Interleukin-18.

Dynamics are often critical for biomolecular function. Herein we explore the role of motion in driving the maturation process of pro-IL-18, a potent pro-inflammatory cytokine that is cleaved by caspases-1 and -4 to generate the mature form of the protein. An NMR dynamics study of pro-IL-18, probing time scales over 12 orders of magnitude and focusing on 1H, 13C, and 15N spin probes along the protein backbone and amino-acid side chains, reveals a plastic structure, with millisecond time scale dynamics occurring in a pair of β-strands, β1 and β*, that show large structural variations in a comparison of caspase-free and bound pro-IL-18 states. Fits of the relaxation data to a three-site model of exchange showed that the ground state secondary structure is maintained in the excited conformers, with the side chain of I48 that undergoes a buried-to-exposed conformational change in the caspase-free to -bound transition of pro-IL-18, sampling a more extensive range of torsion angles in one of the excited states characterized, suggesting partial unpacking in this region. Hydrogen exchange measurements establish the occurrence of an additional process, whereby strands β1 and β* locally unfold. Our data are consistent with a hierarchy of dynamic events that likely prime pro-IL-18 for facile caspase binding.

Preparation of pH-Responsive Kas@ZnO Quantum Dots for Synergistic Control of Rice Blast and Enhanced Disease Resistance in Rice.

The construction of controlled-release formulations improves the sustained-release performance and utilization efficiency of pesticides, which are important aspects in plant protection and environmental chemistry. The current study employs kasugamycin (Kas), which is widely used to control Magnaporthe oryzae, conjugated with carboxyl-functionalized ZnO quantum dots via amide linkages to yield a pH-responsive pesticide delivery system (Kas@ZnO). Physicochemical characterizations indicated the successful preparation of the Kas@ZnO nanoparticles. In vitro drug release assessments indicated that Kas@ZnO exhibited a loading capacity of 21.05% and could effect the controlled release of Kas in an acidic environment, which is beneficial given the unique acidic microenvironment of M. oryzae. Bioactivity assays demonstrated that Kas@ZnO could simultaneously inhibit mycelial growth and spore germination. Additionally, bioactivity tests showed that the control efficacy of Kas@ZnO against rice blast reached 67.43% after 14 days of in vivo spray inoculation, which was higher than that obtained with Kas (55.50%), suggesting improved beneficial effects of Kas@ZnO application over a prolonged duration. Moreover, Kas@ZnO enhanced the activity of defense-related enzymes in rice and upregulated the expression of defense-related genes, such as OsPR2, OsPR3, OsPR5, OsWRKY45, OsLYP6, and OsNAC4. Ultimately, the biosafety assessments revealed that Kas@ZnO did not exert any harmful effects on rice and demonstrated slight toxicity toward zebrafish. These findings indicate that Kas@ZnO can function as a pH-sensitive pesticide delivery system, allowing for targeted release of the pesticide within plant tissues. This technology demonstrates significant potential for eco-friendly plant disease management.

Arginine-Biofunctionalized Ternary Hydrogel Scaffolds of Carboxymethyl Cellulose–Chitosan–Polyvinyl Alcohol to Deliver Cell Therapy for Wound Healing

Wound healing is important for skin after deep injuries or burns, which can lead to hospitalization, long-term morbidity, and mortality. In this field, tissue-engineered skin substitutes have therapy potential to assist in the treatment of acute and chronic skin wounds, where many requirements are still unmet. Hence, in this study, a novel type of biocompatible ternary polymer hybrid hydrogel scaffold was designed and produced through an entirely eco-friendly aqueous process composed of carboxymethyl cellulose, chitosan, and polyvinyl alcohol and chemically cross-linked by citric acid, forming three-dimensional (3D) matrices, which were biofunctionalized with L-arginine (L-Arg) to enhance cellular adhesion. They were applied as bilayer skin biomimetic substitutes based on human-derived cell cultures of fibroblasts and keratinocytes were seeded and grown into their 3D porous structures, producing cell-based bio-responsive hybrid hydrogel scaffolds to assist the wound healing process. The results demonstrated that hydrophilic hybrid cross-linked networks were formed via esterification reactions with the 3D porous microarchitecture promoted by foam templating and freeze-drying. These hybrids presented chemical stability, physicochemical properties, high moisture adsorption capacity, surface properties, and a highly interconnected 3D porous structure well suited for use as a skin substitute in wound healing. Additionally, the surface biofunctionalization of these 3D hydrogel scaffolds with L-arginine through amide bonds had significantly enhanced cellular attachment and proliferation of fibroblast and keratinocyte cultures. Hence, the in vivo results using Hairless mouse models (an immunocompromised strain) confirmed that these responsive bio-hybrid hydrogel scaffolds possess hemocompatibility, bioadhesion, biocompatibility, adhesiveness, biodegradability, and non-inflammatory behavior and are capable of assisting the skin wound healing process.

An Enabling Peptide Ligation Induced by Thiol-Salicylaldehyde Ester for Chemical Protein Synthesis.

Chemical protein synthesis by amide-forming ligation of two unprotected peptide segments offers an effective strategy for the preparation of protein derivatives that are not accessible through bioengineering approaches. Herein, an unprecedented chemical ligation between peptides with C-terminal 2-mercaptobenzaldehyde (thiol-salicylaldehyde, TSAL) esters and peptides bearing N-terminal cysteine/penicillamine is reported. Reactive peptide TSAL esters can be obtained from peptide hydrazides in an operationally simple and highly effective manner. This chemoselective peptide ligation enables the rapid production of N,S-benzylidene acetal intermediates, which can readily be converted into native amide bonds even at sterically hindered junctions. In addition, the current method can be applied compatibly in concert with other types of ligations and subsequent desulfurization chemistry, thereby facilitating convergent protein synthesis. The effectiveness of this new method is also showcased by the total synthesis of proteins ubiquitin and hyalomin-3 (Hyal-3), the efficient synthesis of protein ubiquitin-fold modifier 1 (UFM1) via a C-to-N sequential TSAL ester-induced ligation strategy, and the chemical synthesis of protein Mtb CM through a combined strategy of Ser/Thr ligation and TSAL ester-induced ligations.

Deciphering Spectroscopic Signatures of Competing Ca2+ - Peptide Interactions.

Calcium-protein interactions are of paramount importance in biochemistry. They are a key element in a number of biological processes, such as neuronal signaling. Therefore, an understanding of the interaction at the molecular level is highly desirable. Here, we study the zwitterionic model peptide l-alanyl-l-alanine (2Ala), which has two distinct and competing binding sites for Ca2+: The carbonyl of the peptide bond and the C-terminus, the carboxylate group. We perform linear and two-dimensional IR spectroscopy experiments and find that the spectroscopic signatures of both moieties in the IR spectra change in amplitude and peak position upon the addition of CaCl2: A blueshift of the asymmetric carboxylate band and a redshift for the amide I mode. Ab initio molecular dynamics simulations confirm the direct interaction of the Ca2+ ion at both the carboxylate and the amide CO site leading to different spectral responses. The blueshift of the asymmetric carboxylate band is caused by a localization of the charge, leading to a decoupling of the CO stretching modes of the carboxylate group. The slight redshift of the amide I mode of 2Ala upon the addition of CaCl2 contrasts the blueshift that has been observed for isolated amide motifs, such as N-methylacetamide (NMA). This difference is caused by the smaller number of water molecules being replaced by the Ca2+ ion for 2Ala's amide compared to less sterically hindered, isolated amide carbonyls, in conjunction with vibrational Stark effects. Our results highlight the importance of considering potential competing binding sites, such as the amide CO backbone, the termini and residues, as well as the nature of the hydration of both peptide and ion, when exploring ions' interacting with small peptides and larger proteins.

A Multifunctional Additive for Long‐Cycling Lithium‐Sulfur Batteries Under Lean‐Ether‐Electrolyte Conditions

AbstractThe failure of lithium‐sulfur (Li‐S) batteries operating under lean‐ether‐electrolyte conditions can be ascribed to the deterioration of electrolytes, the passivation of cathodes, and the degeneration of lithium anodes. Efforts to address these challenges by exploring alternative electrolytes beyond commonly used ether‐based systems often introduce new complications. In this study, the utilization of a multifunctional additive, 2‐Bromoacetamide (BA), for ether electrolytes is proposed to achieve stable Li‐S batteries under lean‐electrolyte conditions. These investigations reveal that the amide bond in BA forms hydrogen bonds with sulfur atoms, promoting the dissolution of lithium sulfides (Li2S) in ether electrolytes and mediating the conversion of lithium polysulfides. This enhanced solubility of Li2S facilitates 3D deposition (vertical to the substrate) rather than the typical 2D deposition (parallel to the substrate) of Li2S, and thus alleviates the passivation of cathodes. Furthermore, the incorporation of BA promotes uniform and dense lithium deposition. The use of the BA‐containing electrolyte enables stable cycling of a Li‐S pouch cell for 40 cycles, even under a low electrolyte‐to‐sulfur ratio of 4 µL mg−1. This multifunctional strategy offers an effective solution to extend the lifetime of Li‐S batteries under lean‐electrolyte conditions, thereby paving the way for practical applications of Li‐S battery technology.

Conductance Channels in a Single-Entity Enzyme.

For a long time, the prevailing view in the scientific community was that proteins, being complex macromolecules composed of amino acid chains linked by peptide bonds, adopt folded structure with insulating or semiconducting properties, with high bandgaps. However, recent discoveries of unexpectedly high conductance levels, reaching values in the range of dozens of nanosiemens (nS) in proteins, have challenged this conventional understanding. In this study, we used scanning tunneling microscopy (STM) to explore the single-entity conductance properties of enzymatic channels, focusing on bilirubin oxidase (BOD) as a model metalloprotein. By immobilizing BOD on a conductive carbon surface, we discern its preferred orientation, facilitating the formation of electronic and ionic channels. These channels show efficient electron transport (ETp), with apparent conductance up to the 15 nS range. Notably, these conductance pathways are localized, minimizing electron transport barriers due to solvents and ions, underscoring BOD's redox versatility. Furthermore, electron transfer (ET) within the BOD occurs via preferential pathways. The alignment of the conductance channels with hydrophilicity maps, molecular vacancies, and regions accessible to electrolytes explains the observed conductance values. Additionally, BOD exhibits redox activity, with its active center playing a critical role in the ETp process. These findings significantly advance our understanding of the intricate mechanisms that govern ETp processes in proteins, offering new insights into the conductance of metalloproteins.

De(sulfon)amidative Cyclization: The Synthesis of Dibenzolactams and Dibenzosultams for Organic Light Emitting Diode Materials

This study addresses a challenge in organic synthetic chemistry: the direct cleavage of amide bonds, which is typically hampered by the thermodynamic stability of the C(Ar)–C(acyl) bond. Previous methods often rely on “CO” extrusion‐jointing transition metal‐catalyzed process and require activated tertiary amides, limiting their applicability due to incompatibility with reactive functional groups such as halogens. Herein, we report a transition metal‐free approach for the deamidative cyclization of biaryl diamides via a radical process, yielding dibenzolactam derivatives. Along this line, we have developed the desulfonamidative cyclization of biaryl disulfonamides to produce dibenzosultams through direct nucleophilic aromatic substitution, demonstrating high selectivity for unsymmetrical structures. Additionally, unsymmetrical sulfamoyl biaryl amides, containing both amide and sulfonamide functionalities, can selectively undergo desulfonamidative coupling with the amide to form dibenzolactams, which offers a complementary synthetic pathway to unsymmetric dibenzolactams. These protocols exhibit excellent compatibility with reactive functional groups, including halogens, providing an innovative synthetic toolbox for the development of thermally activated delayed fluorescence (TADF) materials used in organic light emitting diodes (OLEDs). DMAC‐PDO, incorporating a dibenzolactam as the acceptor unit, serves as an efficient blue TADF emitter with a maximum external quantum efficiency (EQEmax) of 23.4%.