Latest ArticlesPhotodynamic therapy (PDT) has emerged as a promising approach for tumor treatment due to its non-invasiveness and high selectivity. However, the off-target activation of phototoxicity and the limited availability of tumor-specific biomarkers pose challenges for effective PDT. Here, we present the development of a novel ratiometric near-infrared-Ⅱ (NIR-Ⅱ) fluorescent organic nanoprobe, BTz-IC@IR1061, which responds specifically to hypochlorite (HClO) within tumors. This nanoprobe allows ratiometric fluorescence imaging to monitor and guide activated tumor PDT. BTz-IC@IR1061 nanoparticles were synthesized by codoping the small molecule dye BTz-IC, which generates reactive oxygen species (ROS), with the commercial dye IR1061. The presence of HClO selectively activates the fluorescence and photodynamic properties of BTz-IC while destroying IR1061, enabling controlled release of ROS for tumor therapy. We demonstrated the high selectivity of the nanoprobe for HClO, as well as its excellent photostability, photoacoustic imaging capability, and photothermal effects. Furthermore, in vivo studies revealed effective tumor targeting and remarkable tumor growth inhibition through tumor-activated PDT. Our findings highlight the potential of BTz-IC@IR1061 as a promising tool for tumor-specific PDT, providing new opportunities for precise and controlled cancer therapy.
Chemical modification of native peptides and proteins is a versatile strategy to facilitate late-stage diversification for functional studies. Among the proteogenic amino acids, lysine is extensively involved in post-translational modifications and the binding of ligands to target proteins, making its selective modification attractive. However, lysine’s high natural abundance and solvent accessibility, as well as its relatively low reactivity to cysteine, necessitate addressing chemoselectivity and regioselectivity for the Lys modification of native proteins. Although Lys chemoselective modification methods have been well developed, achieving site-selective modification of a specific Lys residue remains a great challenge. In this review, we discussed the challenges of Lys selective modification, presented recent examples of Lys chemoselective modification, and summarized the currently known methods and strategies for Lys site-selective modification. We also included an outlook on potential solutions for Lys site-selective labeling and its potential applications in chemical biology and drug development.
The bioactive constituents found in natural products (NPs) are crucial in protein-ligand interactions and drug discovery. However, it is difficult to identify ligand molecules from complex NPs that specifically bind to target protein, which often requires time-consuming and labor-intensive processes such as isolation and enrichment. To address this issue, in this study we developed a method that combines ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry (UHPLC-ESI-MS) with molecular dynamics (MD) simulation to identify and observe, rapidly and efficiently, the bioactive components in NPs that bind to specific protein target. In this method, a specific protein target was introduced online using a three-way valve to form a protein-ligand complex. The complex was then detected in real time using high-resolution MS to identify potential ligands. Based on our method, only 10 molecules from green tea (a representative natural product), including the commonly reported epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), as well as the previously unreported eepicatechin (4β→8)-epigallocatechin 3-O-gallate (EC-EGCG) and eepiafzelechin 3-O-gallate-(4β→8)-epigallocatechin 3-O-gallate (EFG-EGCG), were screened out, which could form complexes with Aβ1–42 (a representative protein target), and could be potential ligands of Aβ1–42. Among of them, EC-EGCG demonstrated the highest binding free energy with Aβ1–42 (−68.54 ± 3.82 kcal/mol). On the other side, even though the caffeine had the highest signal among green tea extracts, it was not observed to form a complex with Aβ1–42. Compared to other methods such as affinity selection mass spectrometry (ASMS) and native MS, our method is easy to operate and interpret the data. Undoubtedly, it provides a new methodology for potential drug discovery in NPs, and will accelerate the research on screening ligands for specific proteins from complex NPs.
The overuse of surfactants has made them well-known environmental pollutants. So far, it is still a challenge to simultaneously distinguish cationic, anionic, zwitterionic, nonionic surfactants and surfactants with similar structures based on traditional analytical techniques. We developed a high-throughput method for distinguishing various surfactants based on the adaptive emission profile as fingerprints (AEPF). The fluorescence response of the sensor was based on the interaction between surfactants and 1,3-diacetylpyrene (o-DAP) probe. The interaction affected the reversible conversion of free molecules and two aggregates in the solution, thereby changing the relative abundance and the fluorescence intensity ratio of two aggregates emitting different fluorescence. The o-DAP sensor can distinguish four types of surfactants (16 surfactants), especially surfactants of the same type with similar structures. The o-DAP sensor sensitively determined the critical micelle concentration (CMC) of 16 surfactants based on the interaction between o-DAP and surfactants. Additionally, the o-DAP sensor can detect and distinguish artificial vesicles made from different surfactants.
Severe traumatic bone healing relies on the involvement of growth factors. However, excessive supplementation of growth factors can lead to ectopic ossification and inflammation. In this study, utilizing the neural regulatory mechanism of bone regeneration, we have developed a multifunctional three dimensions (3D) printed scaffold containing both vasoactive intestinal peptide (VIP) and nerve growth factor (NGF) as an effective new method for achieving bone defect regeneration. The scaffold is provided by a controlled biodegradable and biomechanically matched poly(lactide-ethylene glycol-trimethylene carbonate) (PLTG), providing long-term support for the bone healing cycle. Factor loading is provided by peptide fiber-reinforced biomimetic antimicrobial extracellular matrix (ECM) (B-ECM) hydrogels with different release kinetics, the hydrogel guides rapid bone growth and resists bacterial infection at the early stage of healing. Physical and chemical characterization indicates that the scaffold has good structural stability and mechanical properties, providing an ideal 3D microenvironment for bone reconstruction. In the skull defect model, compared to releasing VIP or NGF alone, this drug delivery system can simulate a natural healing cascade of controllable release factors, significantly accelerating nerve/vascular bone regeneration. In conclusion, this study provides a promising strategy for implanting materials to repair bone defects by utilizing neuroregulatory mechanisms during bone regeneration.
Biomolecular condensates, also known as membraneless organelles, play a crucial role in cellular organization by concentrating or sequestering biomolecules. Despite their importance, synthetically mimicking these organelles using non-peptidic small organic molecules has posed a significant challenge. The present study reports the discovery of D008, a self-assembling small molecule that sequesters a unique subset of RNA-binding proteins. Analysis and screening of a comprehensive collection of approximately 1 million compounds in the Chinese National Compound Library (Shanghai) identified 44 self-assembling small molecules in aqueous solutions. Subsequent screening of the focused library, coupled with proteome analysis, led to the discovery of D008 as a small organic molecule with the ability to condensate a specific subset of RNA-binding proteins. In vitro experiments demonstrated that the D008-induced sequestration of RNA-binding proteins impeded mRNA translation. D008 may offer a unique opportunity for studying the condensations of RNA-binding proteins and for developing an unprecedented class of small molecules that control gene expression.
Diabetic kidney disease (DKD) is recognized as a severe complication in the development of diabetes mellitus (DM), posing a significant burden for global health. Major characteristics of DKD kidneys include tubulointerstitial oxidative stress, inflammation, excessive extracellular matrix deposition, and progressing renal fibrosis. However, current treatment options are limited and cannot offer enough efficacy, thus urgently requiring novel therapeutic approaches. Tetrahedral framework nucleic acids (tFNAs) are a novel type of self-assembled DNA nanomaterial with excellent structural stability, biocompatibility, tailorable functionality, and regulatory effects on cellular behaviors. In this study, we established an in vitro high glucose (HG)-induced human renal tubular epithelial cells (HK-2 cells) pro-fibrogenic model and explored the antioxidative, anti-inflammatory, and antifibrotic capacity of tFNAs and the potential molecular mechanisms. tFNAs not only effectively alleviated oxidative stress through reactive oxygen species (ROS)-scavenging and activating the serine and threonine kinase (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway but also inhibited the production of pro-inflammatory factors such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in diabetic HK-2 cells. Additionally, tFNAs significantly downregulated the expression of Collagen I and α-smooth muscle actin (α-SMA), two representative biomarkers of pro-fibrogenic myofibroblasts in the renal tubular epithelial-mesenchymal transition (EMT). Furthermore, we found that tFNAs exerted this function by inhibiting the Wnt/β-catenin signaling pathway, preventing the occurrence of EMT and fibrosis. The findings of this study demonstrated that tFNAs are naturally endowed with great potential to prevent fibrosis progress in DKD kidneys and can be further combined with emerging pharmacotherapies, providing a secure and efficient drug delivery strategy for future DKD therapy.
A computer-assisted chemical investigation of an intriguing photoreaction of norditerpenoids (3‒7) has been first reported, leading to not only their biomimetic conversion, but also the generation of several new products with uncommon 4,14-dioxabicyclo[10.2.1]pentadecane scaffold (8, 9, 12‒14). In bioassay, compounds 10 and 15 exhibited significant stimulation of GLP-1 secretion. This study has given an insight for the application of computational methods on the late-stage skeleton transformation of complex natural products towards new bioactive compounds.
Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients, oxygen, and biomolecules from the surrounding microenvironments. Inspired by natural processes, tumor biomineralization has evolved due to its biocompatibility, self-reinforcing capability, and penetration-independent mechanism. However, the selective induction of tumor biomineralization using synthetic tools presents a significant challenge. Herein, a metabolic glycoengineering-assistant tumor biomineralization strategy was developed. Specifically, the azido group (N3) was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz. In addition, a bisphosphonate-containing polymer, dibenzocyclooctyne-poly(ethylene glycol)-alendronate (DBCO-PEG-ALN, DBPA) was synthesized, which attached to the tumor cell surface via "click chemistry" reaction between DBCO and N3. Subsequently, the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments, triggering a consecutive process of biomineralization. This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner, suggesting its potential as an effective anti-tumor strategy for in vivo applications.
The aggressive nature and high mortality rate of lung cancer underscore the imperative need for early diagnosis of the disease. Thus, aminopeptidase N (APN), a potential biomarker for lung cancer, should be thoroughly investigated in this context. This report describes the development of HA-apn, a novel near-infrared fluorescent probe, specifically engineered for the sensitive detection of endogenous APN. Characterized by its high selectivity, straightforward molecular architecture, and suitable optical properties, including a long-wavelength emission at 835 nm and a large Stokes shift of 285 nm, HA-apn had high efficacy in identifying overexpressed APN in tumor cells, which shows its potential in pinpointing malignancies. To further validate its applicability and effectiveness in facilitating the direct and enhanced visualization of pulmonary alterations, an in situ lung cancer mouse model was employed. Notably, HA-apn was applied for in vivo imaging of APN activity in the lung cancer mouse model receiving the probe through aerosol inhalation, and rapid and precise diagnostic results were achieved within 30 min post-administration. Overall, HA-apn can be applied as an effective, non-intrusive tool for the rapid and accurate detection of pulmonary conditions.
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