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63 papers

Synthesis, Characterization, Antioxidant Evaluation, Cytotoxicity Studies, and Molecular Docking of Novel Sulfonamide Derivatives.

Bouraoui O et al. · Jul 1, 2026

A series of novel sulfonamide derivatives (4a-i) was synthesized via a three-step sequence involving Schiff base formation, sodium borohydride reduction to the corresponding secondary amines (2a-i), and subsequent treatment with p-toluenesulfonyl chloride in the presence of sodium carbonate. The structures of all intermediates and final products were unambiguously confirmed by FT-IR, 1 H NMR, 13 C NMR, and HRMS analyses. The antioxidant activity of the target compounds was assessed using the DPPH radical scavenging assay with BHT as a reference standard. Among the synthesized derivatives, compound 4d exhibited the most pronounced antioxidant activity, surpassing BHT at concentrations of 37.5 and 62.5 µg/mL. The cytotoxicity of the compounds was evaluated against human ovarian carcinoma (A2780) and prostate cancer (LNCaP) cell lines using the MTT assay, with docetaxel as a positive control. Compounds 4g, 4h, and 4i demonstrated the highest cytotoxic potency against both cell lines, with compound 4h displaying a log IC 50 value of 1.343 µg/mL against LNCaP cells. Structure-activity relationship analysis suggests that the methoxy substituent enhances cytotoxic activity, likely through increased lipophilicity and electron-donating effects facilitating interactions with biological targets. Molecular docking studies were performed to further rationalize the observed biological activities.

Biochemistry, Genetics and Molecular Biology

Reductive Methylation: An Alternative to Lysine → Arginine Mutagenesis.

Molina OJ et al. · Jul 1, 2026

Modification of lysine residues is a common strategy in protein engineering, whether to prevent posttranslational modifications, control bioconjugation, or improve crystallization. The standard genetic approach-replacement with arginine by site-directed mutagenesis-preserves positive charge but alters other physicochemical attributes and cannot address the N-terminal amino group. Here, we characterize reductive methylation as a chemical alternative. This reaction converts every primary amino group to a dimethylamino group rapidly under mild aqueous conditions. Using human ribonuclease 1 and a cytotoxic variant engineered to evade the endogenous ribonuclease inhibitor as model systems, we assess the effects of complete dimethylation on thermostability, enzymatic catalysis, protein-protein interaction, compatibility with bioconjugation, cellular uptake, and intracellular persistence. Dimethylation preserves thermostability and a protein-protein interaction. Enzymatic catalysis, in contrast, is reduced by 10 2 - to 10 3 -fold, consistent with the role of catalytic lysine residues. Dimethylation is fully compatible with bioconjugation chemistry. Dimethylated and unmodified ribonucleases show comparable uptake and persistence in human cells. These findings establish reductive methylation as a practical and conservative strategy for lysine modification in protein and peptide engineering and support its use in applications such as biological proteolysis-targeting chimeras (bioPROTACs).

Biochemistry, Genetics and Molecular Biology

Pegargiminase Suppresses the Fanconi Anemia Pathway and Promotes Melphalan-Induced DNA Double-Strand Breaks in Uveal Melanoma.

Pavlyk I et al. · Jul 1, 2026

Uveal melanoma is a hard-to-treat arginine-dependent cancer secondary to argininosuccinate synthetase 1 (ASS1) loss with half of patients succumbing to liver-dominant metastases. Arginine deprivation with pegargiminase is a novel antimetabolite strategy for patients with uveal melanoma. We investigated the preclinical rationale for combining pegargiminase with melphalan, an alkylating agent approved recently for the treatment of hepatic-centric disease. Drug sensitivity of ASS1-deficient uveal melanoma cell lines was performed in 2D culture using proliferation and cytotoxicity assays, with analysis of cell death, cell cycle, DNA double-strand breaks, and interrogation of the molecular mechanism of action by RNA-seq. ADI-PEG20 and melphalan suppressed uveal melanoma cell line proliferation and triggered cytotoxicity, effects which were enhanced with the drug combination. ADI-PEG20 downregulated multiple genes of the Fanconi anemia pathway and synergized with melphalan to increase DNA double-strand breaks. Melphalan and pegargiminase is a rational new drug combination that warrants clinical testing in uveal melanoma.

Biochemistry, Genetics and Molecular Biology

Elliptical β-barrel deformation underlies gating in VDAC1.

Bergdoll L et al. · Jul 1, 2026

Gating by voltage-dependent anion channels (VDAC) regulates mitochondrial metabolite flux, yet the structural mechanism underlying the open-to-closed transition remains unresolved. Here, we combine atomistic molecular dynamics (MD) simulations with double electron-electron resonance (DEER), using hydrostatic pressure as a reversible thermodynamic perturbation to shift conformational equilibria and stabilize low-population states. MD simulations reveal localized intrinsic flexibility within β-strands β1-β5 and β19, as well as in cytosolic loops connecting β6-β7 and β8-β9. High-pressure DEER measurements in lipid nanodiscs corroborate these predictions, identifying reversible, pressure-dependent distance changes within the pore lumen consistent with asymmetric deformation of the β-barrel. DEER-informed analysis of unbiased MD trajectories reveals an elliptical β-barrel conformation aligned parallel to the N-terminal helix that corresponds to the pressure-stabilized experimental state. ATP permeation simulations identify a free-energy barrier to metabolite translocation in this elliptical geometry, whereas diffusion through the circular open state is energetically favorable. These findings indicate that the elliptical conformation represents a transient gating-competent state rather than a fully closed channel. Together, our results support a gating mechanism driven by reversible β-barrel deformation and establish pressure-perturbed DEER integrated with MD as a general strategy for capturing transient, functionally relevant conformations of membrane channels.

Biochemistry, Genetics and Molecular Biology

Oxidative Stress Induced Senescent Macrophage-Driven Squamous Cell Carcinoma Invasion via Glutamine Metabolic Reprogramming.

Wang S et al. · Jul 1, 2026

Oxidative stress drives tumor microenvironment (TME) remodeling by inducing metabolic reprogramming and cellular senescence. Glutamine, a key substrate supporting oxidative stress defense, has been implicated in TME remodeling and metastasis, yet its specific role in initiating tumor invasion remains unclear. Here, oxidative stress induced the generation of senescent macrophages in the TME, and clinical samples showed that their accumulation positively correlates with malignancy. We established cisplatin- and radiation-induced senescent macrophage models that exhibited distinct senescence-associated secretory phenotypes (SASP) and enhanced squamous cell carcinoma (SCC) migration and invasion. Integrated metabolomic and transcriptomic analyses revealed the glutamine-glutamate pathway as a central metabolic hub, with glutaminase 2 upregulated to drive glutaminolysis and strongly associated with IL-1β expression. Mechanistically, IL-1β secreted by senescent macrophages promoted tumor invasion by downregulating IL-1R2 and activating NF-κB signaling in SCC cells. Targeting the glutamine metabolism-regulated IL-1β/IL-1R2 axis effectively suppressed SCC invasion. These findings uncover a novel metabolic mechanism linking glutamine metabolism to SASP regulation and suggest a therapeutic strategy to limit SCC invasion.

Biochemistry, Genetics and Molecular Biology

Fine structural tuning of the assembly of elastin-collagen peptide conjugates with drug loading and manipulation of molecular interactions.

Huang H et al. · Jul 1, 2026

Elastin-collagen nanoparticles (ECnPs) have been shown in our previous studies to self-assemble into different morphologies, including nanoplates and nanovesicles, by manipulating the sequence length of the elastin-like peptide (ELPs) and collagen-like peptide (CLPs) of a given conjugate. In this work, we demonstrate that the morphologies of ECnPs can also be modulated, for a given ECnP sequence, with variations in solution pH and/or the amount of encapsulated drug. Specifically, the peptide (VPGYG) 6 -(GPO) 8 preferentially formed nanovesicles under basic conditions but assembled into nanoplates under acidic conditions. Another sequence, (VPGWG) 2 (VPGFG) 2 -(GPO) 8 , produced nanovesicles when loaded with a high concentration of dexamethasone-carboxyfluorescein (Dex-CF), but transitioned to nanoplates at lower drug loading. Furthermore, in addition to the different morphologies observed for a given set of initial solution conditions, our studies also illustrate the possibility of triggering vesicle-to-plate transformations for a given ECnP with release of Dex-CF over time. These results highlight multiple avenues for controlling ECnP morphology, expanding their applicability as a flexible and efficient drug delivery platform.

Biochemistry, Genetics and Molecular Biology

Fix or freeze? Spectral differences arising from tissue preparation in chemical imaging.

Zheng T et al. · Jun 29, 2026

Spectrochemical imaging has emerged as a powerful, label-free modality for visualizing the biochemical composition of tissues based on intrinsic vibrational signatures. Specifically, mid-infrared spectrochemical imaging (MIRSI) is becoming essential for fundamental biomedical research studying disease mechanisms, identifying biomarkers, and guiding drug development. However, the sensitivity of MIRSI to sample preparation protocols and its impact on spectral data interpretation remain poorly characterized. Here, we systematically compared spectral data collected from rat kidney and liver tissues prepared using standard fresh frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) tissue processing methods using quantum cascade laser (QCL)-based MIRSI. We applied frequently used spectral data processing techniques, including uniform manifold approximation and projection (UMAP), correlation matrices, and second-derivative spectral analysis to characterize preparation-induced differences. FF samples preserved a broader range of biochemical signals, retaining the innate chemical composition of tissues, while FFPE tissues showed reduced spectral diversity and absorption signal intensity. Moreover, we observed a consistent spectral band at 1026 cm -1 primarily in FFPE samples, likely arising from fixation-induced chemical modifications and/or structural rearrangements. Our findings demonstrate that tissue preparation substantially alters chemical and morphological information captured by MIRSI, necessitating careful consideration of processing protocols in workflows involving chemical imaging and Artificial Intelligence (AI)-based spectral analysis.

Biochemistry, Genetics and Molecular Biology

Severe Pediatric Snakebite With Coagulopathy and Compartment Syndrome: Conservative Management With Plasma Exchange.

Al Muqbel ZM et al. · Jun 25, 2026

Snakebite envenomation is a global public health concern, and hemotoxic bites can lead to severe coagulopathy, microangiopathic hemolytic anemia, and compartment syndrome. We describe a previously healthy 6-year-old boy who presented with progressive left lower limb swelling, discoloration, and bleeding from intravenous cannula sites following a snakebite sustained in rural Pakistan, consistent with severe hemotoxic envenomation. Despite antivenom and transfusion support, he developed persistent venom-induced consumption coagulopathy with hypofibrinogenemia, markedly prolonged clotting times, thrombocytopenia, and features of microangiopathic hemolytic anemia. Severe limb swelling raised concern for compartment syndrome; however, fasciotomy was deferred due to the high risk of bleeding in the setting of uncontrolled coagulopathy. Transferred to Bahrain, he underwent five sessions of therapeutic plasma exchange, initiated due to ongoing clinical and laboratory deterioration, resulting in stabilization of hematologic parameters, resolution of limb swelling, and preservation of limb function. This case highlights the role of plasma exchange in children unresponsive to conventional therapy and demonstrates that conservative management of suspected compartment syndrome may be feasible when surgical intervention carries significant risk, underscoring the importance of early recognition and multidisciplinary care in complex pediatric envenomation.

Biochemistry, Genetics and Molecular Biology

SynaptoTagMe, a toolkit for in vivo mapping and modulating neurotransmission at single-cell resolution.

Cuentas-Condori A et al. · Jun 25, 2026

Understanding the organization and regulation of neurotransmission at the level of individual neurons and synapses requires tools that can track and manipulate transmitter-specific vesicles in vivo. Here, we present SynaptoTagMe, a suite of genetic tools in Caenorhabditis elegans to fluorescently label and conditionally ablate the vesicular transporters for glutamate, GABA, acetylcholine, and monoamines. Using a structure-guided approach informed by protein topology and evolutionary conservation, we engineered endogenously tagged versions for each transporter that maintain their physiological function while allowing for cell-specific, bright, and stable visualization. We also developed conditional knockout strains that enable targeted disruption of neurotransmitter synthesis or packaging in single neurons. We applied this toolkit to map co-expression of vesicular transporters across the C. elegans nervous system, revealing that over 10% of neurons exhibit co-transmission. Using the ADF sensory neuron as a case study, we demonstrate that serotonin and acetylcholine are trafficked in partially distinct vesicle pools. Our approach provides a powerful platform for mapping, monitoring, and manipulating neurotransmitter identity and use in vivo. The molecular strategies described here are likely applicable across species, offering a generalizable approach to dissect synaptic communication in vivo.

Biochemistry, Genetics and Molecular Biology

The structural chemistry and biosynthesis of chlorophylls.

Hunter CN et al. · Jun 25, 2026

Chlorophylls (Chls) harvest the solar energy that drives photosynthesis, which underpins most of the food chains on our planet. Starting from protoporphyrin IX, just seven biosynthetic reactions culminate in the synthesis of Chl a , the major light-absorbing pigment on Earth. Other such pigments, Chls b , c , d and f , widen the absorption range in the visible and red regions of the spectrum, and several bacteriochlorophylls (BChls), BChls a , b and g in particular, open new spectral windows allowing organisms to harvest near infra-red light. This perspective surveys the structural features of porphyrins, chlorins and bacteriochlorins that impart their characteristic absorption features, then presents a similar analysis of the biosynthetic intermediates leading to Chls a , b , c , d and f . The interlinked Chl and BChl biosynthetic pathways are summarised, then the rest of the perspective focusses on the enzymes that synthesise Chls a , b , c , d and f . AlphaFold 3 was used to model a complete set of structures for Chl biosynthesis enzymes, predicting intersubunit associations and the arrangements of cofactors and bound substrates, and providing insights into catalytic mechanisms. A new scheme for binding substrates and transferring products between pathway enzymes suggests how synthetic biology approaches can assemble hybrid Chl and BChl pathways to expand the spectral range for harvesting and using solar energy.

Biochemistry, Genetics and Molecular Biology