ChemBioChem最新文献

Bacterial biofilms are structured microbial communities embedded in a self-produced extracellular matrix, displaying enhanced tolerance and, in many cases, resistance to biocides, antimicrobial agents, and host immune responses. These traits make biofilms a major driver of chronic and recurrent infections, which are increasingly difficult to eradicate and represent a significant global health challenge in the context of rising antimicrobial resistance (AMR). Biofilms are recognized as surface and nonsurface-attached aggregates in diverse clinical, industrial, and environmental settings, broadening our knowledge of their ecological and physiological diversity. Surfactants have emerged as promising antibiofilm agents due to their dual functionality: the capacity to disrupt the extracellular matrix and their inherent antimicrobial activity. Among them, amino acid-based surfactants, particularly cationic derivatives such as those based on arginine, combine potent biocidal effects with favorable biocompatibility and environmental sustainability. These compounds offer a persuasive alternative to conventional biocides, which often promote cross-resistance and environmental concerns. This review integrates current knowledge of biofilm formation and persistence with advances in the development and application of amino acid-based surfactants as antibiofilm agents. Sustainable synthesis of these compounds, as well as mechanistic insights, and the translational challenges of moving from in vitro assays to real-world scenarios in the AMR era.

Traditional biocatalytic cascades typically require discrete enzymes for each synthetic step. Here, we report unprecedented trifunctional imine reductases (IRED) that conduct three sequential transformations-alkene reduction, intramolecular reductive amination, and imine reduction-all within a single catalytic cycle. This elegant single-enzyme catalytic system directly transforms linear substrates into enantiomerically pure 2-aryl pyrrolidines via a concerted cascade without intermediate isolation. Combining density functional theory (DFT) calculations and mechanistic studies, we elucidate how the IRED achieves step-selective catalysis. Our findings establish a proof-of-concept for simplifying complex biocatalytic cascades using multifunctional enzymes, offering a powerful strategy to streamline synthetic pathways.

The O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

The rippled β-sheet was predicted by Linus Pauling and Robert Corey in 1953. Unlike the closely related pleated β-sheet, which rapidly expanded to become common textbook knowledge, the rippled β-sheet remained obscure for decades. The critical body of biophysical evidence for the structural viability of this neglected motif only began to emerge in the 2000s and onwards. The first crystal structure of a rippled β-sheet was reported by our laboratory in 2022, that is, 69 years since its original prediction. From model tripeptides, we gradually expanded to longer, biologically relevant sequences. Subsequent rational molecular design led to the creation of chimeric mixed chirality peptides capable of forming rippled sheets from single components (i.e., "self-rippling" peptides), as well as rippled sheet macrocycles. Over half of the canonical amino acid alphabet has meanwhile been observed in the context of the rippled β-sheet. The number of ripple-genic amino acids keeps expanding as the field continues to mature. The rippled β-sheet is a platform that allows readily accessing a wide variety of aggregated peptidic folds, often with unique properties. The field is wide open for discovery.

Aromatic rings bearing amino groups provide natural products with structural diversity and potent biological activities. Although aromatic amination is a useful reaction in organic synthesis, knowledge of biological aromatic amination remains limited. In this study, we identified an unprecedented nitrite-dependent aromatic amination in nybomycin biosynthesis. By comparing biosynthetic gene clusters whose products have a diamino phenol scaffold, we hypothesized that nine genes, including two nitrite biosynthetic genes, are responsible for the biosynthesis of this scaffold. Using heterologous expression in Streptomyces albus, we identified the minimum number of enzymes required for 2,4-diamino-3-hydroxybenzoic acid (2,4,3-DAHBA) biosynthesis. Further analysis revealed that three enzymes (NybN, NybO, and NybC) were responsible for converting 3-hydroxyanthranilic acid (3-HAA) into 2,4,3-DAHBA using nitrite. In vitro assays revealed that NybO, an ATP-dependent ligase, catalyzes the diazotization of 3-HAA to form 2-diazo-3-hydroxybenzoic acid (2,3-DHBA) and that NybC, an NADPH-dependent oxidoreductase, catalyzes the reduction of 2,3-DHBA to form 2-hydrazino-3-hydroxybenzoic acid. Taken together with other experimental results, we propose two possible biosynthetic pathways for 2,4,3-DAHBA synthesis from 3-HAA. This study provides important insights into nitrite-mediated aromatic amination, expanding the availability of nitrite for natural product biosynthesis.

The Bcl-2 protein Bcl-xL is an inhibitor of intrinsic apoptosis which either directly inhibits the pore-forming Bcl-2 proteins, like Bax or Bak, or indirectly inhibits pore formation by sequestering the pro-apoptotic BH3-only activators. The structural basis of the inhibition of pore formation in the outer mitochondrial membrane is still largely unknown due to the lack of atomic resolution structures of the relevant inhibitory complexes at the membrane. Herein, a protocol to obtain high-yield recombinant monomeric full-length Bcl-xL proteins is presented. The monomeric Bcl-xL retains the ability to shuttle between membrane and aqueous environments and can successfully inhibit Bcl-2-induced membrane permeabilization via both modes of action, as proven by in vitro and in organelle assays with a minimal Bcl-2 interactome constituted by Bcl-xL, cBid, and Bax.

The α2-6sialylation of N-acetylglucosamine (Neu5Acα2-6GlcNAc) is an atypical sialylation linkage that has attracted increasing attention due to its unusual occurrence and biological importance. Although relatively rare, it has been identified in human milk oligosaccharides (HMOs), glycoproteins, and glycosphingolipids. Early chemical methodologies and recent chemoenzymatic advances have enabled the preparation of bioactive molecules containing the Neu5Acα2-6GlcNAc motif, thereby facilitating studies of their roles in immune recognition, cancer progression, and neonatal health. This Concept highlights recent progress in synthetic strategies to access structures containing this atypical motif and discusses its emerging significance as both a subject of fundamental glycobiology and a potential target for biomedical applications.

Antibiotic resistance has become a critical global threat, creating an urgent need for new antibacterial agents. Among therapeutic modalities, small-molecule antibacterials offer significant advantages, including controllable metabolism and flexible structural design, making them an excellent platform for combating drug-resistant bacteria. This review highlights recent progress in organic small-molecule antibacterials and is organized into three sections: antibiotics, natural products and their derivatives, and other synthetic small-molecule agents (including heterocyclic, sulfonamide, and amphiphilic compounds). Each section summarizes recent advances in the field, and the review concludes by discussing future directions and challenges in small-molecule antibiotic development. By drawing on strategies across these categories, this overview provides researchers in the field with a fresh perspective to inspire novel approaches and accelerate the development of new antibacterial drugs.

Enhanced proteasome activity is known to confer resistance to cellular stress in vitro and in vivo, but such effects have largely been achieved through genetic upregulation of proteasome subunits and assembly factors. Here, we investigate whether small-molecule 20S proteasome activators can modulate XBP1 signaling during IRE1-driven unfolded protein response (UPR) activation. We show that pre-treatment with a 20S activator prior to IRE1 induction significantly attenuates XBP1 signaling, whereas treatment after chemical induction of IRE1 produces no detectable effect. These findings indicate that proteasome activators can bolster proteasome activity under endoplasmic reticulum (ER) stress, but their ability to modulate an ongoing UPR is limited. This work highlights a potential temporal window in which proteasome activation may influence stress-adaptive signaling.

Nonsteroidal anti-inflammatory drugs are among the most prescribed worldwide to treat pain, fever, and inflammation. However, they can cause severe adverse effects such as gastric, duodenal, hepatic, and renal injuries. Thus, the search for effective and new drugs is of high priority. Herein, the synthesis of a new series 4-((5-substituted-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl) pyrimidin-2-substituted (pyrazole–pyrimidines) obtained through the cyclocondensation reaction of pyrazole–enaminones with amidines under mild conditions is reported. The chemical structures are confirmed by ¹H and ¹³C NMR, mass spectrometry, and single-crystal X-ray analysis for compounds 4c and 4g. Molecular docking studies are conducted to identify selective cyclooxygenase-2 (COX-2) inhibitors, revealing that compounds 4d, 4j, and 4k display higher binding affinity. ADMET predictions (absorption, distribution, metabolism, excretion, and toxicity) corroborate to the docking results, suggesting favorable pharmacokinetic and toxicological properties. The in vivo antinociceptive activity is investigated in mice using the capsaicin-induced nociception model. Oral administration of compounds 4d, 4e, 4f, 4j, and 4k significantly reduces nociceptive responses, achieving effects comparable or superior to celecoxib, without altering locomotor activity. Altogether, the findings demonstrate that pyrazole–pyrimidine derivatives, especially 4d and 4k, are promising candidates for the development of selective COX-2 analgesics, combining antinociceptive efficacy with a favorable toxicological profile.