ChemBioChem最新文献

Radionuclide therapy is expected to be a powerful tool for glioma treatment. Here, we introduced a novel nuclear nanomedicine based on polydopamine (PDA), incorporating fibroblast activation protein inhibitor (FAPI) and macrocyclic chelator (DOTA) for specific cancer targeting and ¹⁷⁷Lu labeling. The synthesized nanoradiopharmaceutical, ¹⁷⁷Lu-DOTA-PEG-PDA-FAPI, exhibits good stability in serum, saline and PBS over 5 days. ¹⁷⁷Lu-DOTA-PEG-PDA-FAPI shows efficient specific uptake and internalization when incubated with U87MG cells. In vivo distribution visualized prominent accumulation and long retention ability of ¹⁷⁷Lu-DOTA-PEG-PDA-FAPI at tumor sites after local administration. Moreover, ¹⁷⁷Lu-DOTA-PEG-PDA-FAPI has satisfactory antitumor ability without apparent toxic and side effects observed from therapy assay and H&E staining. This study highlights the feasibility of using PDA as a nanocarrier for glioma endoradiotherapy by targeting fibroblast activation protein.

Metal-based drugs have the potential to significantly improve therapeutic efficacy by exhibiting key properties such as appropriate charge, thermodynamic stability, hydrolytic stability, oral bioavailability, and dual functional capability. These properties are critical for effective intracellular uptake, as drugs or prodrugs must cross cellular membranes to target specific organelles like mitochondria, essential for maximizing therapeutic impact. Bio-essential metal ions such as copper, zinc, and iron are transported through specialized active channels, whereas others depend on passive diffusion to enter cells. Vanadium has gained significant attention in research because of its remarkable coordination flexibility, lipid-lowering characteristics, and potential anticancer effects. The coordination flexibility of vanadium has led to its investigation in pharmaceuticals, given its demonstrated insulin-mimetic effects, lipid-lowering properties, and promising antitumor activities. Photodynamic therapy (PDT) offers a targeted cancer treatment approach through light-activated compounds that selectively generate reactive oxygen species (ROS) to induce cell death. Among metal-based photosensitizers, vanadium complexes are emerging as effective agents due to their unique redox properties and known biological activity. This minireview explores mitochondria-targeting vanadium complexes within PDT. Mitochondria serve as an ideal ROS generation site, triggering apoptosis while minimizing damage to healthy cells. We examine key strategies in designing vanadium complexes that enhance mitochondrial localization, photodynamic efficiency, and cytotoxic effects on cancer cells. This review highlights the challenges like photostability and selective targeting, and future directions for advancing vanadium-based photosensitizers as next-generation PDT cancer therapies.

Expansion microscopy (ExM) is an innovative super-resolution imaging technique that utilizes physical expansion to magnify biological samples, facilitating the visualization of cellular structures that are challenging to observe using traditional optical microscopes. The fundamental principle of ExM revolves around employing a specialized hydrogel to uniformly expand biological samples, thereby achieving super-resolution imaging under conventional optical imaging conditions. This technology finds application not only in various biological samples such as cells and tissue sections, but also enables super-resolution imaging of large biological molecules including proteins, nucleic acids, and metabolite molecules. In recent years, numerous researchers have delved into ExM, resulting in the continuous development of a range of derivative technologies that optimize experimental protocols and broaden practical application fields. This article presents a comprehensive review of these derivative technologies, highlighting the utilization of ExM for anchoring nucleic acids, proteins, and other biological molecules, as well as its applications in biomedicine. Furthermore, this review offers insights into the future development prospects of ExM technology.

Human antigen R (HuR) is an RNA binding protein (RBP) belonging to the ELAV (Embryonic Lethal Abnormal Vision) family, which stabilizes mRNAs and regulates the expression of multiple genes. Its altered expression or localization is related to pathological features such as cancer or inflammation. Dihydrotanshinone I (DHTS I) is a naturally occurring, tetracyclic ortho-quinone inhibitor of the HuR-mRNA interaction. Our earlier efforts led to the identification of a synthetic Tanshinone Mimic (TM) 2 with improved affinity for HuR. Here we report five new TM probes 3-5 bearing a detection-promoting moiety (either photo affinity probe - PAP or biotin) as a para-substituent on the phenyl-sulphonamide for mechanism of action (MoA) studies. Biological and biochemical assays were used to characterize the novel TM conjugates 3-5. They showed similar toxic activity in HuR-expressing triple-negative breast cancer MDA-MB-231 cells, with micromolar CC₅₀s. REMSAs revealed that photoactivatable groups (4 a and 4 b), but not biotin (5 a and 5 b), prevented conjugates' ability to disrupt rHuR-RNA complexes. Further biochemical studies confirmed that biotinylated probes, in particular 5 a, can be used to isolate rM1 M2 from solutions, taking advantage of streptavidin-coated magnetic beads, thus being the most promising HuR inhibitor to be used for further MoA studies in cell lysates.

Poly-L–lysine (PLL) displays a high solubilizing ability for hydrophobic guest molecules, and when in complexes with guest molecules, it exhibits a high intracellular uptake. However, its high cytotoxicity, originating from its cationic character, significantly limits its applications in biological and medicinal chemistry. In this study, the amount of free PLL in an aqueous solution of a PLL–porphyrin complex was immensely reduced, resulting in considerably lower dark toxicity than that of the free PLL. Furthermore, the PLL–porphyrin complex exhibited high photodynamic activity under photoirradiation at 610–740 nm.

Multiphoton excited fluorescence (MPEF) imaging has emerged as a powerful tool for visualizing biological processes with high spatial and temporal resolution. Metal-organic frameworks (MOFs), a class of porous materials composed of metal ions or clusters coordinated with organic ligands, have recently gained attention for their unique optical properties and potential applications in MPEF imaging. This review provides a comprehensive overview of the design, synthesis, and applications of multiphoton excited fluorescence imaging using MOFs. We discuss the principles behind the fluorescence behavior of MOFs, explore strategies to enhance their photophysical properties, and showcase their applications in bioimaging. Additionally, we address the current challenges and future prospects in this rapidly evolving field, highlighting the potential of multiphoton excited fluorescence imaging by MOFs for advancing our understanding of complex biological processes.

The most recurrent familial cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of an abnormal number of intronic GGGGCC (G₄C₂) repetitions in the C9orf72 gene, which has been proposed to drive ALS/FTD pathogenesis. Recently, it has been shown that such G₄C₂ repetitions can fold into G-quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small-molecule binders, furnishing proof-of-principle that targeting these non-canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing in silico investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related C9orf72 G4-binders. Moreover, we investigated the binding properties of a strong and selective metal-based G4 stabilizer, the Au^I bis-N-heterocyclic carbene (NHC) complex - Au(TMX)₂ - showing that it moderately stabilizes G₄C₂ G4 RNA by Förster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)₂ binding mode and the associated free-energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS/FTD neurodegenerative disorders.

The development of artificial metalloenzymes (ArMs) offers a potent approach to incorporate non-natural chemical reactions into biocatalysis. Here we report the assembly of Mn(salen)-based ArMs by embedding biotinylated Mn(salen) complexes into streptavidin (Sav) variants. Using commercially available nitrene and oxo transfer reagents, these biohybrid catalysts catalyzed the aziridination of alkenes and oxidation of benzylic C-H bonds with up to 19 and 146 turnover numbers.

The biotinylated probes based on anticancer saponin OSW-1 with varied linker lengths were synthesized and their cell growth inhibitory activity and affinity pulldown efficiency were evaluated. All probes demonstrated comparable cytotoxicity to the parent natural product, highlighting that the linker moiety had a minimal impact on cell uptake or target engagement. In contrast, when evaluated against the known target proteins, OSBP and ORP4, the biotinylated probe 3 with PEG5 linker enabled most effective enrichment of target proteins in the affinity pulldown assay, suggesting that the cytotoxicity and pulldown efficiency did not correlate among the probes studied. Our data provided the first evidence that OSW-1 specifically binds to endogenously expressed OSBP and ORP4. The selectivity of affinity pulldown using probe 3 was also validated by facile identification of the enriched protein by silver staining and LC/MS analysis. Therefore, probe 3 with PEG5 linker comprising of 25 atoms (28 Å) was found as an optimal biotinylated probe for isolating OSW-1 binding proteins from cell lysate.

We have examined in this contribution the electrostatic interactions between single arginine and aspartic acid by analyzing the peptide-peptide binding characteristics involving arginine-aspartic acid, arginine-glycine, arginine-tryptophan and tryptophan-glycine interactions. The results of aspartic acid mutagenesis revealed that the interactions between arginine and aspartic acid have significant dependence on the position and composition of amino acids. While the primary interaction can be attributed to arginine-tryptophan contacts originated from the indole moieties with the main chains of 14-mers containing N−H and C=O moieties, pronounced enhancement could be identified in association with the electrostatic side-chain-side-chain interactions between arginine and aspartic acid. An optimal separation of 2~4 amino acids between two adjacent aspartic acid and tryptophan binding sites can be identified to achieve maximal enhancement of binding interactions. Such observed separation dependence may be utilized to unravel cooperative effects in heterogeneous interactions between single pair of amino acids.