Search Results (450)

Janus kinase 2 (JAK2) occupies a central position in cytokine signaling and plays essential roles in hematopoiesis, immune regulation, and cancer. Although recent advances in structural biology, cryo-EM, receptor modeling, and biophysical analysis have substantially expanded current views of JAK2 function, key mechanistic questions remain regarding how receptor geometry, JH2-mediated autoinhibition, and disease-associated mutations are structurally integrated. In this review, we discuss the multidomain organization of JAK2 and examine how the FERM–SH2 module, the pseudokinase domain (JH2), and the catalytic kinase domain (JH1) cooperate to govern receptor specificity, allosteric control, and cytokine-induced activation. We further analyze how pathogenic mutations rewire this regulatory system by weakening autoinhibitory contacts, altering linker-mediated communication, or stabilizing active dimeric conformations. Finally, we assess current and emerging therapeutic strategies, from ATP-competitive inhibitors to macrocyclic and JH2-selective allosteric modulators, with emphasis on how structural insight can guide next-generation drug design. These advances support a more integrated view of JAK2 regulation and define new opportunities for selective therapeutic intervention. Full article

Background/Objectives: Cyclotides are plant-derived macrocyclic peptides distinguished by their head-to-tail cyclized backbone and cystine knot motif, which confer remarkable stability against thermal, enzymatic, and chemical degradation. These features, combined with a compact and rigid structure, position cyclotides as promising scaffolds for future antibacterial agents in response to the escalating threat of multidrug-resistant (MDR) pathogens and the stagnation of conventional antibiotic discovery pipelines. This review summarizes the structural features, antibacterial mechanisms, bioengineering strategies, and translational potential of cyclotides against MDR infections. Methods: A narrative review of the literature was conducted using recent original research articles and reviews on cyclotide structure, antibacterial activity, bioengineering, computational modeling, and pharmaceutical applications. Results: Cyclotides exhibit potent antimicrobial activity, primarily through membrane disruption mediated by amphipathic surfaces and affinity for anionic bacterial membranes. Some variants also demonstrate anti-virulence and antibiofilm properties, broadening their therapeutic relevance for difficult-to-treat infections. Bioengineering approaches, including epitope grafting and rational design, have improved selectivity and potency while reducing cytotoxicity. Advances in computational modeling, molecular dynamics, and artificial intelligence have accelerated the prediction and optimization of antimicrobial activity, toxicity, and pharmacokinetic properties. Conclusions: Innovations in synthesis, including recombinant expression and enzymatic ligation, are helping overcome translational barriers related to cost and scalability. Although challenges remain in oral bioavailability and systemic delivery, strategies such as lipidation and scaffold modification support the development of cyclotide-based therapeutics as adaptable platforms for peptide drug discovery. Full article

Background: The NLRP3 inflammasome drives pathological inflammation in various diseases. PINK1/Parkin-associated mitophagy serves as a critical negative regulator of NLRP3 activation, yet pharmacological enhancers remain scarce. Muscone, a natural macrocyclic ketone with blood–brain barrier permeability, exhibits potent anti-inflammatory properties; however, its mechanistic role within the NLRP3-mitophagy axis remains undefined. Methods: LPS/ATP-stimulated macrophages were employed to assess stage-specific effects of muscone on NLRP3 priming (NF-κB signaling, NLRP3, and pro-IL-1β expression) and activation (ASC oligomerization, ASC–pro-caspase 1 complex formation, and IL-1β secretion). RNA sequencing and bioinformatic analysis were performed for pathway enrichment. Mitophagy was characterized by MitoSOX Red staining for mt-ROS detection, electron microscopy, Western blotting of LC3B-II in isolated mitochondria and PINK1 and Parkin in whole-cell lysates, and live-cell mitochondria–lysosome tracking. In vivo protective efficacy was assessed in an LPS-induced endotoxemia mouse model. Results: Muscone dose-dependently suppressed both the priming and activation stages of the NLRP3 inflammasome, maximally reducing IL-1β secretion by ~60% at 50 μM. Mechanistically, muscone amplified PINK1/Parkin-associated mitophagy, scavenging excessive mt-ROS and attenuating NLRP3 activation. These effects were corroborated by RNA-seq and comprehensive functional assays. In vivo, muscone (30 mg/kg) significantly improved survival (3/8 mice alive at 98 h when all LPS controls had died; 2/8 survived to the 132-h endpoint), with concomitant enhancement of mitophagy markers in peritoneal macrophages. Conclusions: Muscone functions as a PINK1/Parkin-associated mitophagy enhancer that maintains mitochondrial quality control during NLRP3-driven inflammatory responses. Its unique macrocyclic structure and blood–brain barrier permeability provide a promising scaffold for developing therapeutics against inflammatory disorders associated with NLRP3 inflammasome activation. Full article

Structural parameters for over seventy complexes of the composition Cu(η²-X^1×2)(Y³) or Cu(κ²-X¹X²)(Y³) were analyzed in this work, being the third of a series of structural studies on three coordinated copper(I) complexes. Bidentate (X¹X²) with monodentate (Y³) donor ligands build up distorted trigonal planar coordination spheres around copper(I) atoms. The bidentate ligands (X¹X²) create three-, four-, and five-membered metallocyclic rings. The three-membered are: -C¹-C²-Cu-C³; -B¹=B²-Cu-Cl³; -P≡C²-Cu-C³, -B¹-B²-Cu-X³, and B¹-C²-Cu-C³. The X¹-Cu-X² angles indicate a total mean value of 44.2°. The four-membered complexes are -H¹-B(H₂)-H²-Cu-C³; -H¹-B(Ph₂)-H²-Cu-C³; -O¹AlO²-Cu-N³; -O¹CeO²-Cu-N³; -S¹CP²-Cu-C³; -N¹PN²-Cu-C³; -N¹PS²-Cu-P³; -N¹SiO¹-Cu-Cl³; --N¹CS²-Cu-C³; -Si¹-NSi²-Cu-C³, and O¹CO²-Cu-C³, and show a total mean value of the L-Cu-L angles of 71.0°. The five-membered are: -N¹-C=C-N²-Cu-Y³ (more common) and N=C-C=N-Cu-C³. In this group, there are also copper(I) complexes in which the central Ns of five-membered metallocycle are “interlocked” in macrocycles. The X¹-Cu-X² angles exhibit an average value of 82.9°. There is a wide variety of monodentate (Y³) ligands in the studied complexes. The mean value of Cu-Y³ elongates with covalent radius (Å) of coordinate atoms in the sequence: 1.846(13) Å (N³, 0.75) < 1.884(21) Å (O³, 0.73) < 1.928(18) Å (C³, 0.77) < 2.126(18) Å (Cl³, 0.99) < 2.140(5) Å (S³, 1.02) < 2.194(4) Å (P³, 1.06) < 2.246(12) Å (Br³, 1.14) < 2.2445(18) Å (I³, 1.33). The data show that angular distortion from regular trigonal geometry grows in the following order: five-, four-, and three-membered. Full article

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article

This case report documents the multi-season development of a 38-year-old elite F12 shot putter with macular degeneration (<10% functional vision) who improved from 13.00 m to a personal best of 14.41 m between 2021 and 2023. Athletes classified as F11–F13 compete with significant visual impairment that limits spatial feedback during rotational tasks, yet longitudinal evidence describing integrated training frameworks remains scarce. A 12-month macrocycle integrated phase-dependent velocity-based resistance training using mean concentric velocity targets (0.70–1.00 m·s⁻¹) monitored via linear position transducers with a 10% velocity loss threshold, combined with structured auditory and tactile cueing, including metronome pacing and environmental anchors. High-volume warm-ups and prehabilitation addressed a prior L4–L5 disk herniation. The athlete achieved 14.41 m at the 2023 U.S. Para Athletics Trials, with TrackMan^®-verified release velocity of 11.3 m·s⁻¹. Bench throw velocity improved by 35.4% (0.65 to 0.88 m·s⁻¹) and squat jump velocity improved by 22.9% (1.18 to 1.45 m·s⁻¹), while post-session RPE remained manageable, indicating improved neuromuscular readiness and training tolerance. No lumbar symptom recurrence occurred. This case illustrates that integrating velocity autoregulation, multisensory stabilization, and injury-informed preparation can support meaningful performance gains in visually impaired throwers and offers an applied framework for coaches working with F11–F13 athletes. Full article

Background/Objectives: Due to the widespread problem of antimicrobial resistance (AMR), there is an urgent need to identify new antibacterial targets that act through mechanisms distinct from those of existing antibiotics. One of these targets is the essential cell division protein FtsQ, which is a central hub of the Gram-negative divisome, but the druggability of its extensive protein–protein interaction (PPI) interfaces remains poorly defined. Here, we present a comprehensive structure-based in silico characterization of Escherichia coli FtsQ aimed at identifying and prioritizing druggable regions for PPI modulation. Methods: We analyzed E. coli FtsQ in both apo and complexed states (FtsQB, FtsQL, and FtsQBL) using a combination of pocket-mapping tools (FTMap and SiteMap), evolutionary conservation analysis (ConSurf), and structure property assessment (BLAST, ProBiS) to map and evaluate potential binding pockets of FtsQ protein. Results: Eight potential binding sites were predicted across the β and POTRA domains of FtsQ. One previously unreported site within the POTRA domain was prioritized as a candidate site, characterized by favorable druggability scores, strong evolutionary conservation, and a putative role in the FtsQ–FtsW/FtsN/FtsI interaction network. In contrast, two highly conserved sites at the FtsQ–FtsB/FtsL interaction interface were structurally flat, indicating limited suitability for classical small-molecule binding and greater compatibility with alternative modalities such as macrocycles or peptidomimetics. Conclusions: Although FtsQ lacks deep canonical binding pockets, this study proposes several conserved and potentially tractable regions as candidate sites, supporting its potential as a non-classical but promising antibacterial target for disrupting bacterial cytokinesis. Full article

Two metallacyclic tetranuclear Fe(III) complexes, [{Fe₂(μ-O)(μ-RCOO)₂(tpon)}₂](BPh₄)₄ [R = Me (1), Ph (2)], where the flexible ditopic ligand tpon (N,N,N′,N′-tetrakis(2-pyridylmethyl)octane-1,8-diamine) links two μ-oxo-bis(μ-carboxylato) triple-bridged dinuclear units, have been prepared. Single-crystal X-ray diffraction establishes that both complexes adopt a 26-membered macrocyclic framework featuring an internal cavity capable of guest inclusion. Notably, incorporation of a monoatomic μ-oxo bridge enforces an outward orientation of the ligand alkyl chains, thereby suppressing the “zipper effect” observed in the previously reported Mn(II) analogue and facilitating the encapsulation of an acetone molecule. UV–vis absorption and diffuse-reflectance spectra confirm that the tetranuclear scaffold remains intact in both the solid state and in solution. These results demonstrate that modulating local coordination directionality via μ-oxo bridging is an effective strategy for controlling the global conformation and host–guest properties of large metallasupramolecular architectures. Full article

Cyclodepsipeptides constitute a structurally diverse class of natural products composed of amino acid and hydroxy acid residues interconnected through both amide and ester bonds. Among them, xylaroamide A, a cyclic heptadepsipeptide, was recently identified from an endolichenic Xylaria species via a molecular networking-guided discovery approach. Despite xylaroamide A exhibiting intriguing structural features and notable bioactivity potential, its total synthesis has thus far remained unexplored. Herein, we report the first total synthesis of xylaroamide A, achieved through a hybrid solid/solution-phase synthetic approach. The linear precursor was assembled in accordance with the native amino acid sequence via Fmoc-based solid-phase peptide synthesis, incorporating the preassembled ester fragment at a later stage of assembly. Subsequent macrocyclization took place under high-dilution conditions to furnish the target cyclodepsipeptide. The structure of the synthetic product was confirmed by means of optical rotation and NMR and MS spectroscopic analyses, which exhibited good agreement with the reported data for the natural product. This work establishes a reliable and efficient synthetic route to xylaroamide A and provides a foundation for further bioactivity and structure optimization investigations. Full article

Curvularins, a class of macrocyclic lactones, have cytotoxic, antimicrobial, and anti-inflammatory properties. Curvularin, a 12-membered macrolactone, was used as a scaffold to design and synthesize structurally modified analogues to investigate structure–activity relationships and improve biological efficacy. Three series of curvularin-based analogues, Cur-5H-OMe, Cur-4P-OMe, and Cur-OMe, were synthesized with the same core structure but different substituent sizes and positions. Nine representative derivatives were evaluated for anti-inflammatory, anticancer, antibacterial, and antifungal activities. In LPS-stimulated RAW 264.7 macrophages, most compounds inhibited nitric oxide (NO) production in a concentration-dependent manner but exhibited cytotoxicity at high concentrations. Cytotoxicity assays against HaCaT cells and human cancer cell lines (HCT116, HeLa, and A375) revealed limited selectivity toward cancer cells. Antimicrobial evaluation indicated selective activity against the Gram-positive bacteria, Staphylococcus aureus. Compound 23 exhibited superior antibacterial potency compared with kanamycin and notable antifungal activity against Candida albicans. This study provides a versatile synthetic platform and identifies key structural features of curvularin derivatives, demonstrating their potential as anti-inflammatory and antimicrobial lead compounds. Full article

Dirofilaria immitis constitutes a significant global veterinary burden and an emerging zoonotic risk. Despite decades of study, the structural evolution of its scientific landscape remains unexplored. This study provides a comprehensive longitudinal analysis of global research on D. immitis to evaluate its trajectory, intellectual structure, and conceptual shifts over the last eight decades. A systematic bibliometric analysis was conducted following PRISMA guidelines adapted for bibliometrics. Data were retrieved from Web of Science Core Collection and Scopus, covering the period from 1945 to 2025. After deduplication and manual screening, a final corpus of 3589 documents was analyzed using performance indicators and science mapping techniques to assess growth patterns, geographic leadership, collaboration networks, and thematic evolution. The field exhibits a mature profile with a sustained mean annual growth rate of 2.39%. Production is geographically polarized, with the United States and Italy acting as the primary research hubs, though international collaboration networks are increasingly integrating endemic regions in the Global South. Thematic analysis reveals a profound paradigm shift: while early research (1945–1980) focused on parasite morphology and clinical description, the 21st century is characterized by a multidisciplinary approach dominated by molecular biology, the study of the endosymbiont Wolbachia, and the genetic mechanisms of macrocyclic lactone resistance. The intellectual structure is currently organized into distinct but interconnected clusters, linking established clinical pathology with emerging genomic and environmental control strategies. Research on D. immitis has evolved from a classical parasitology discipline into a complex biomedical ecosystem aligned with the One Health framework. The persistence of the disease, driven by drug resistance and climate-mediated vector expansion, has catalyzed a transition toward integrative research models. Future control strategies must transcend geographic borders, combining advanced genomic surveillance with ecological modeling to mitigate the impact of this transboundary disease on both animal and human health. Full article

In recent years, metal phthalocyanine (MPc)-based sensors have garnered significant interest for applications in environmental monitoring, biomedical diagnostics, and industrial process control, owing to their efficient and cost-effective sensing capabilities. In contrast to conventional inorganic materials, MPcs are a class of small-molecule materials characterized by a stable, π-conjugated macrocyclic framework with a tunable central metal ion. This structural architecture imparts unique physicochemical properties, including high chemical stability, excellent redox activity, structural versatility, considerable dielectric constant and electrical conductivity, along with pronounced optical absorption and excellent environmental stability. By incorporating different metal ions into the macrocyclic core, their functional characteristics can be precisely modulated to achieve high sensitivity and selectivity toward various gas, ion, or biomolecule targets. Leveraging these advantages, MPcs have been extensively utilized in diverse sensing platforms, such as photoelectric, gas, and biosensors. This review outlines recent advances in MPc-based sensor research and provides perspectives on their future development trends. Full article

Nickel(II) and palladium(II) ions are capable of forming complexes with macrocyclic terapyrrole structures such as the porphyrin or corrin ring. Many different derivatives of these complexes are synthesized and studied because these compounds have potential numerous applications, including catalysis, various light-driven chemical reactions and processes related to intramolecular and intermolecular energy redistribution. Nickel porphyrins exhibit neither fluorescence nor phosphorescence when excited with light; however, palladium porphyrins, when excited to the singlet state, very quickly transform into the triplet state, and unlike nickel porphyrins, deactivation of the excited states occurs by phosphorescence. Palladium corrin has dual luminescent properties and exhibits both a weak fluorescence and strong phosphorescence. These photophysical differences are based on the complex energetic redistribution of singlet and triplet excited states interacting with each other in the intersystem crossing process. Based on the results of calculations at the DFT/TDDFT and CASSCF/NEVPT2 levels of theory, the structure of electronic excited states of model nickel(II) and palladium(II) complexes with corrin and porphyrin macro-rings was characterized and potential paths of photophysical processes leading to the occupancy of low-lying triplet states were described. In nickel complexes, very low-energy triplet states are the main cause of the rapid radiationless deactivation of excited states via triplet photophysical pathways. Full article

Ethylene cross-bridged tetraazamacrocycles have been used to stabilize first-row transition metal complexes for applications under harsh conditions, such as biomedical imaging and aqueous oxidation catalysis. We have applied these ligands to the synthesis of complexes of a larger second row transition metal, namely, square pyramidal Pd²⁺ complexes, which may be useful for future catalytic processes. We now report the synthesis and crystal structure determination of four novel Pd²⁺ complexes of the general formula [PdLCl]PF₆, where L is the dimethyl ethylene cross-bridged derivative of 12aneN4 (cyclen), 13aneN4 (homocyclen), or 14aneN4 (cyclam), or the dibenzyl ethylene cross-bridged derivative of 14aneN4 (cyclam). Solid-state structures of all four complexes can be described as a distorted square pyramidal with τ₅ values ranging from 0.01 to 0.20, with three macrocycle nitrogen atoms and one chloride in the square base and the fourth ligand nitrogen constrained by the cross-bridge to the axial position. Cyclic voltammetry of the complexes in acetonitrile shows stabilization of the Pd³⁺ oxidation state by all four complexes. Electronic spectroscopy reveals the typical behavior for square pyramidal Pd²⁺. Full article

The discovery of structurally novel anti-tumor agents remains a crucial objective in cancer drug research. In this study, we systematically explored the bioactivity potential of sarocladione (5), a structurally unique marine-derived 14-membered ring diketone steroid. Guided by a function-oriented strategy, seven new derivatives (6–13) were synthesized based on an efficient biomimetic synthesis of sarocladione. Evaluation of their antiproliferative activities against human cancer cell lines demonstrated that the intact macrocyclic scaffold is indispensable for activity. Extension of the conjugated π-system led to the identification of compound 8, which exhibited approximately four-fold enhanced potency against HCT116 cells (IC₅₀ = 1.86 µM) compared with the parent natural product. Stereochemical analysis further revealed the critical role of the (5R)-configuration at C-5. Phenotypic investigations indicated that compound 8 induces concentration-dependent G2/M phase cell cycle arrest, followed by apoptosis, suggesting a cell cycle-dependent antiproliferative effect. Overall, this study highlights sarocladione as a promising marine-derived scaffold for further antiproliferative optimization. Full article