Background: Metal-based anticancer drugs, particularly platinum and gold complexes, play a central role in chemotherapy but are often limited by systemic toxicity, resistance, and suboptimal selectivity. Peptide conjugation has emerged as a versatile strategy to modulate the pharmacokinetic and biological properties of metal complexes, enabling targeted delivery, improved uptake, and controlled activation. This review aims to critically analyze platinum- and gold-peptide bioconjugates in cancer therapy, focusing on directly reactive metal complexes and redox-activated prodrug systems. Methods: Relevant literature from the past two decades was surveyed across major scientific databases, focusing on the design, conjugation strategies, biological activity, and mechanisms of action of Pt- and Au-peptide bioconjugates. Results: Reviewed studies reveal distinct behavior for platinum- and gold-based systems. Pt(II)-peptide conjugates primarily retain DNA-reactive interaction, with peptides mainly enhancing cellular uptake, selective targeting and solubility, although improved cytotoxicity is not consistently achieved. In contrast, Pt(IV)-peptide conjugates function as prodrugs, where axial peptide functionalization allows greater structural versatility and sometimes improved selectivity, with therapeutic efficacy strongly depending on intracellular reduction kinetics. Au(I)-peptide conjugates act as directly reactive species targeting thiol- and selenol-containing proteins, whereas Au(III) bioconjugates often behave as redox-activated prodrugs, with peptide conjugation influencing stability and cellular fate. Conclusions: Overall, peptide conjugation represents a powerful but non-trivial approach for optimizing metal-based anticancer agents. The success of metal-peptide bioconjugates critically depends on balancing peptide-mediated delivery with the intrinsic reactivity and activation pathways of the metal center. A function-guided design of bioconjugates is essential to achieve genuine selectivity and therapeutic benefit.
Immune checkpoint inhibitors and antibody-drug conjugates have rapidly expanded treatment options for gynecologic malignancies, although the magnitude of benefit varies substantially across tumor types and biomarker-defined populations. This narrative review summarizes the biologic rationale, predictive biomarkers, pivotal clinical trials, regulatory approvals, guideline-supported strategies, and emerging directions for immune checkpoint blockade and antibody-drug conjugates in endometrial, cervical, and ovarian cancers. In endometrial cancer, molecular classification and mismatch repair status have transformed treatment selection, with PD-1 or PD-L1 blockade now integrated into first-line chemoimmunotherapy and recurrent disease management. HER2-directed and TROP-2-directed antibody-drug conjugates are also emerging as biomarker-directed strategies. In cervical cancer, human papillomavirus-driven tumor biology, PD-L1 expression, and tissue factor expression support the use of checkpoint inhibitors, antibody-drug conjugates, and therapeutic vaccine approaches across locally advanced and recurrent or metastatic settings. In ovarian cancer, single-agent checkpoint blockade has shown limited activity in unselected populations, but recent advances include biomarker-selected chemoimmunotherapy in platinum-resistant disease and clinically meaningful activity of folate receptor alpha-directed and HER2-directed antibody-drug conjugates. Across gynecologic cancers, key challenges include refining predictive biomarkers, optimizing sequencing after prior immunotherapy exposure, managing overlapping toxicities, and designing trials that enrich for biologically responsive subgroups. Future progress will depend on integrating molecular classification, immune contexture, ADC target expression, and patient-specific clinical factors into treatment selection.
Background/Objectives: The clinical application of the potent antitumor alkaloid camptothecin is severely limited by its high systemic toxicity, poor solubility, and rapid inactivation. This study aimed to design, synthesize, and evaluate a novel series of camptothecin-lipid conjugates where natural steroids and triterpenoids serve as lipophilic carriers to enhance cellular penetration and mitigate cardiotoxicity. Herein, we implemented an endogenous targeting strategy by conjugating camptothecin with natural steroids and triterpenoids, which serve as biomimetic lipophilic vectors to achieve tumor-selective intracellular delivery. Methods: Eleven novel camptothecin-based hybrids linked via succinic acid or ethylene glycol spacers were synthesized and characterized. Their in vitro cytotoxicity was evaluated against eight cancer cell lines of varied embryologic origin (Jurkat, HCT 116, A549, HL60, K562, HeLa, HEK293, and Fibroblasts). Cell cycle distribution, apoptosis induction, and topoisomerase I inhibitory activity were assessed using flow cytometry and enzyme assays. In silico pharmacokinetic profiling, including P-glycoprotein interaction and cardiotoxicity mitigation, was substantiated via ADME algorithms. Results: Among the series, compounds 12 (cholestanol conjugate) and 26 (betulin derivative) emerged as the primary lead candidates based on an optimal composite of submicromolar cytotoxicity, exceptional tumor selectivity indices (up to 7.0 for 12), and active topoisomerase I inhibition. Compounds 11-14 generally shared prominent S-phase cell cycle arrest, while the lead hybrids 12 and 26 successfully combined high apoptotic triggering with favorable in silico ADME safety profiling, including eliminated cardiotoxicity for the structural analogs. Conclusions: The integration of steroidal and triterpenoid pharmacophores via strategic spacers provides a reliable foundation for developing targeted, low-toxicity camptothecin-lipid conjugates with optimized safety profiles for cancer therapy.
Integrins represent a large family of cell surface receptors that exist as heterodimers with essential roles in key biological processes such as cellular adhesion, motility, and cytokinesis. Among them, integrin beta-6 (IB6), which exclusively dimerizes with integrin alpha-v, has emerged as a clinically relevant target due to its restricted expression in normal adult epithelial tissues and elevated levels in solid tumors. High expression of IB6 is correlated with poor prognosis across multiple solid tumor types. PF-08046876 is an investigational antibody-drug conjugate (ADC) consisting of the anti-IB6 monoclonal antibody conjugated to a camptothecin-class topoisomerase I (TOP1) inhibitor, AMDCPT, using a traceless enzyme-cleavable glucuronide linker. The AMDCPT payload has been optimized for differentiation from other TOP1 inhibitors with improved potency, enhanced bystander activity, and reduced susceptibility to multidrug resistance (MDR) efflux mechanisms. PF-08046876 leverages the same antibody backbone from sigvotatug vedotin (SV) and binds IB6 without cross-reactivity to other alpha-v integrin complexes. In preclinical studies, PF-08046876 has demonstrated significant antitumor activity both in vitro and in vivo across multiple tumor models with IB6 expression, including non-small cell lung (NSCLC), head and neck squamous cell (HNSCC), urothelial (UC), pancreatic (PDAC), and esophageal (ESCA) carcinomas. These findings support further clinical development of PF-08046876 as a promising therapeutic candidate for the treatment of IB6-expressing solid tumors.
Background: The therapeutic potential of many natural products, including curcumin (CUR), betulinic acid (BA), and oleanolic acid (OA), is limited by poor oral exposure caused by low aqueous solubility, metabolic instability, and/or first-pass metabolism. Lipid-drug conjugate (LDC) strategies that mimic endogenous dietary lipid processing may provide a useful approach for improving oral absorption and lymphatic transport. Methods: A 1,3-diolein-based lipidic promoiety (IN-4) was synthesized and conjugated to curcumin, betulinic acid, and oleanolic acid to generate three representative LDCs: CUR-PRO, BA-PRO, and OA-PRO. Their oral pharmacokinetic behavior was evaluated in rats. For CUR-PRO, matched-vehicle comparisons across three oral vehicles were performed, together with mesenteric lymph duct cannulation and in vitro stability/conversion studies in simulated gastrointestinal media, rat liver microsomes, and rat plasma. Results: All three prodrugs were successfully synthesized and showed improved systemic exposure to the corresponding parent-drug-related analytes under the tested conditions. For CUR-PRO, dose-normalized AUC0-last of released curcumin was markedly higher than direct curcumin administration across all three vehicles (increases of 15.0-, 70.9-, and 54.3-fold), and intact CUR-PRO was also detected in plasma. Mesenteric lymph sampling showed that CUR-PRO dosing, but not free-curcumin dosing, generated detectable curcumin-related signals under the present analytical conditions. In vitro, no free curcumin was detected during CUR-PRO incubation in enzyme-free simulated gastrointestinal media; CUR-PRO underwent rapid depletion in pancreatic-lipase-supplemented medium, showed greater microsomal stability than curcumin, and displayed plasma conversion that was markedly accelerated by exogenous LPL. BA-PRO and OA-PRO also increased systemic exposure of their released parent drugs, with 16.0- and 38.4-fold dose-normalized AUC0-last increases, respectively. Conclusions: These findings provide proof-of-concept evidence that 1,3-diolein-based lipidation can improve the oral exposure of selected poorly water-soluble natural products. The lymphatic transport data provide qualitative evidence supporting lymphatic access of CUR-PRO, although the quantitative contribution of this pathway to the overall exposure increase remains to be established.
We developed a smartphone-assisted digital image-based optical biosensor array using a planar glass slide with sensor spots in a 2 × 5 array format for point-of-care multiplex detection of biomarkers. The detection is based on the integration of the capture antibody (AbC)-functionalized sensor array with a detection antibody-conjugated gold nanoparticle bioconjugate (AuNP@AbD) in the presence of interleukin-8 (IL8) to form a sandwich-type AuNP@AbD-IL8-AbC nanocomplex on the sensing spot surface. Thus, the colorimetric detection method can be applied to the quantitative analysis of IL8, a clinically relevant pro-inflammatory and pro-angiogenic biomarker. The sensing strategy utilizes digital image-based analysis via ImageJ software (V 1.54 g; Java 1.8.0_345 [64 - bit], Windows 8) to quantify the colorimetric signals generated by the light absorbance of surface-bound gold nanoparticles in response to an IL8 droplet sample of merely 8 μL on the planar glass surface, achieving a low detection limit of 0.23 pg/mL (27 fM) and good reproducibility with a coefficient of variation of 0.95%. Validation using IL8-spiked serum at concentrations of 1 × 10-9 M and 1 × 10-10 M showed minimal matrix effects with a detection accuracy of 99.5% and 106.1%, respectively. Hence, this low-cost portable digital image-based plasmonic nanoparticle-linked immunosorbent assay serves as an alternative to traditional enzyme-linked immunosorbent assays.
Background/Objectives: Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of breast cancer, expanding treatment opportunities across multiple disease settings. However, their increasing clinical use has revealed a heterogeneous spectrum of toxicities that extends beyond conventional chemotherapy-related adverse events. Emerging evidence suggests that ADC-associated toxicities are driven by a complex interplay between ADC structural characteristics, including target antigen expression, payload properties, linker stability, drug-to-antibody ratio, and patient-related susceptibility factors. This review aims to provide a comprehensive overview of ADC-related toxicities in breast cancer, integrating mechanistic insights with clinical management strategies and risk-adapted approaches. Methods: A narrative review of the literature was conducted focusing on clinical trials, real-world studies, translational investigations, and mechanistic evidence related to ADC-associated toxicities in breast cancer. Particular attention was given to the relationship between ADC design, toxicity mechanisms, patient-specific risk factors, and clinical management. Results: ADC-related toxicities encompass a broad range of adverse events, including hematologic toxicity, interstitial lung disease, gastrointestinal complications, hepatotoxicity, peripheral neuropathy, stomatitis, ocular toxicity, dermatologic adverse events, and cardiovascular manifestations. Current evidence indicates that toxicity profiles differ substantially across ADCs and are influenced by multiple factors, including payload class, linker chemistry, target biology, intracellular trafficking, bystander effects, systemic payload exposure, and host-related characteristics. While several toxicities can be anticipated through careful monitoring and early intervention, clinically significant variability remains, and validated predictive biomarkers are largely lacking. Emerging real-world evidence further highlights the importance of individualized toxicity assessment and multidisciplinary management. Conclusions: ADC-related toxicity should be viewed as a multifactorial biological process resulting from the interaction between ADC design and host susceptibility rather than as a uniform class effect. A mechanistic understanding of toxicity pathways may improve risk stratification, toxicity monitoring, and personalized management strategies. Future research should focus on the development of predictive biomarkers, pharmacologic risk models, and next-generation ADC platforms with improved therapeutic indices. This review proposes an integrated framework linking ADC structural determinants, toxicity mechanisms, and clinical management to support safer and more individualized use of ADCs in breast cancer.
Hematological malignancies account for over 1.3 million new cases and approximately 700,000 deaths annually. Despite advances in targeted therapies, immunotherapies, and antibody-drug conjugates, relapse, refractory disease, and acquired drug resistance remain critical challenges. Peptide-drug conjugates (PDCs) have emerged as a promising targeted delivery platform, combining peptide-mediated specificity with potent cytotoxic payloads. In this review, we summarized the fundamental design principles of PDCs, including targeting peptide selection, linker engineering, and payload optimization, with emphasis on the biological characteristics of hematological malignancies. We then examined current preclinical and clinical progress across multiple myeloma, acute myeloid leukemia, myelodysplastic syndromes, B-cell non-Hodgkin lymphoma, and chronic myeloid leukemia. We further discussed emerging strategies such as cathepsin B-responsive PROTAC-PDC hybrids, nanotechnology-assisted delivery, and artificial intelligence-guided molecular design. Finally, we addressed key translational challenges, including tumor heterogeneity, payload resistance, and pharmacokinetic constraints, and proposed future directions toward biomarker-driven precision PDC therapy for hematological malignancies.
Pancreatic cancer remains one of the most aggressive and lethal malignancies, characterized by late-stage diagnosis, profound molecular heterogeneity, and limited responsiveness to conventional cytotoxic therapies. Recent advances in molecular diagnostics and biomarker-driven treatment stratification have accelerated the development of precision therapeutic approaches aimed at improving outcomes in selected patient populations. This review highlights three mechanistically distinct yet complementary therapeutic strategies that illustrate the evolving landscape of personalized pancreatic cancer management. Adagrasib represents targeted inhibition of oncogenic KRAS G12C signaling, reflecting recent progress in directly targeting historically "undruggable" driver mutations. Dostarlimab illustrates the tissue-agnostic application of immune checkpoint blockade in pancreatic cancers harboring mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), highlighting the growing importance of biomarker-defined immunotherapy-responsive subsets despite the limited pancreatic cancer-specific clinical evidence currently available. Trastuzumab deruxtecan represents a next-generation HER2-directed antibody-drug conjugate (ADC) and demonstrates the potential of HER2-targeted therapy in the small subgroup of patients with HER2-positive pancreatic cancer, although the available evidence is derived primarily from basket trials and tumor-agnostic clinical development. Collectively, these therapeutic approaches underscore the expanding role of biomarker-guided treatment strategies integrating targeted inhibition, immunotherapy, and precision cytotoxic payload delivery. This review summarizes the molecular rationale, available clinical evidence, therapeutic limitations, and resistance mechanisms associated with these approaches while discussing emerging directions in translational research, rational combination strategies, liquid biopsy applications, and precision oncology that may further refine individualized treatment algorithms for pancreatic cancer.
Background/Objectives: Reactive oxygen species (ROS)-responsive polymeric drug conjugates (PDCs) can enable oxidative stress-triggered drug release, but their activation may be limited by heterogeneous or insufficient intracellular ROS. Herein, we synthesized a dual-thioketal-linked PDC bearing two ROS-cleavable thioketal (TK) units in series and combined it with D-α-Tocopheryl polyethylene glycol succinate analog (TPGSa) as a soluble ROS-modulating co-treatment. Methods: PDC was synthesized through stepwise construction of the TK linker and subsequent carbonate coupling with camptothecin (CPT). TPGSa was prepared by esterifying mPEG with tocopheryl succinate. PDC nanoassembly formation, colloidal stability, peroxide-induced structural changes, thiol generation, and CPT release behaviors were evaluated under oxidative conditions. Cytotoxicity was examined in A549 and BEAS-2B cells with intracellular ROS- and CPT-associated fluorescence. Results: PDC formed spherical nanoassemblies with a hydrodynamic diameter of 98.6 ± 2.6 nm and a zeta potential of -13.3 ± 1.2 mV. The PDC remained colloidally dispersed in 10% FBS-containing PBS and after lyophilized storage. Peroxide exposure produced concentration-dependent thiol generation, molecular size change, and CPT release. The PDC + TPGSa reduced A549 viability more than PDC alone, produced the most pronounced dead-cell staining, and yielded the highest intracellular ROS and CPT fluorescence signals. In contrast, BEAS-2B viability remained substantially higher under matched conditions. Conclusions: These findings support an A549-focused in vitro proof of concept in which TPGSa-associated redox perturbation is paired with a dual TK PDC to enhance CPT-associated cytotoxicity.
Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regimen has not yet been investigated. As climate change is associated with earlier and less predictable onset of birch pollen seasons, planned pre-seasonal allergen immunotherapy may unintentionally overlap with natural pollen exposure. Therefore, evaluation of the safety of treatment administered during the pollen season is of increasing clinical relevance. This study aimed to compare, in a purely descriptive manner, the safety and tolerability of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Methods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.: 2022-004082-20), patients (N = 109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10,000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and, thus, before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N = 20). Those who performed the last treatment visit thereafter were assigned to the pre-/co-seasonal group (N = 83). Due to post hoc subgroup allocation and unequal subgroup sizes, all subgroup analyses were purely descriptive. Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N = 3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions, according to the German AWMF classification, were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm; late-phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm; late-phase reactions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N = 89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs appeared descriptively similar between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment-related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well-tolerated, even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.
Objectives: The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the current treatment limitations-particularly the emergence of drug resistance and the reduced efficacy of some existing drugs against new variants-highlight the need for novel antiviral strategies with novel action mechanisms. Fusion inhibitors that disrupt six-helix bundle (6-HB) formation during viral entry represent a promising approach. Posaconazole, an antifungal agent, has been identified as a weak fusion inhibitor, but suffers from poor membrane permeability and modest activity. This study aimed to enhance its antiviral potency by conjugating it with cell-penetrating polyarginine peptides and to investigate the mechanism of action. Methods: A series of posaconazole-polyarginine conjugates were synthesized via click chemistry. Antiviral activity was evaluated using pseudotyped SARS-CoV-2 Omicron XDV in HEK293T cells. Mechanisms were investigated by circular dichroism, native PAGE, size-exclusion HPLC, molecular docking, and isothermal titration calorimetry. Metabolic stability was assessed using hepatic microsomes. Results: Posa-R8 exhibited potent antiviral activity comparable to the clinical candidate EK1, with minimal cytotoxicity. Mechanistic studies confirmed that Posa-R8 binds the HR2 region of the spike protein, disrupts 6-HB formation, and inhibits membrane fusion. It also showed strong lipid bilayer affinity and improved phase I metabolic stability over EK1. Conclusions: Polyarginine conjugation enhances the membrane-binding affinity and antiviral efficacy of posaconazole. Posa-R8 represents a promising lead for developing next-generation SARS-CoV-2 fusion inhibitors.
Telisotuzumab Vedotin (Teliso-V), previously known as ABBV-399, is a novel, first-in-class antibodydrug conjugate developed by AbbVie. It combines an anti-c-Met monoclonal antibody (ABT-700) with monomethyl auristatin E (MMAE), a potent microtubule-disrupting agent, via a cleavable linker. This design allows selective delivery of the cytotoxic payload to c-Met-overexpressing tumour cells, thereby bypassing reliance on MET signalling for efficacy. Preclinical studies demonstrated that ABBV-399 effectively inhibited the growth of xenograft tumors refractory to other MET-targeted inhibitors. In early Phase I trials, the agent showed a favourable safety profile and elicited objective tumour responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. In the Phase II LUMINOSITY study, which served as the basis for accelerated FDA approval, Teliso-V demonstrated an overall response rate (ORR) of 35% and a median duration of response (DOR) of 9 months in patients with high c-Met protein overexpression. Continued approval may depend on confirmatory Phase III data.
Serogroup X has emerged as an important cause of invasive meningococcal disease across Sub-Saharan Africa. Recent advances in serogroup X vaccines were reviewed. Early vaccine development efforts focused on outer membrane vesicle-based approaches. The growing epidemiological importance of serogroup X accelerated the development of serogroup X conjugate vaccines. Building on the success of MenAfriVac, PATH and the Serum Institute of India Pvt. Ltd. developed NmCV-5 (MenFive), the first pentavalent meningococcal conjugate vaccine targeting serogroup X. NmCV-5 achieved World Health Organization (WHO) pre-qualification in 2023, enabling deployment across Sub-Saharan Africa. A second pentavalent vaccine, EuNmCV-5, developed by Eubiologics is advancing through clinical development, while an additional candidate from Sinovac Biotech is entering early phase evaluation. These advances representative a major milestone in meningococcal disease prevention. Within the last fifteen years significant vaccine developments have been made to combat serogroup X. With NmCV-5 attaining WHO pre-qualification, strategies for its implementation within Sub-Saharan Africa are being devised. Only one vaccine is currently available in Sub- Saharan Africa, but trials of a second pentavalent ACWYX conjugate vaccine are ongoing. Carriage studies and disease surveillance are crucial to monitor serogroup X vaccine effectiveness.
Duvelisib (DVB), a selective PI3K-δ/γ inhibitor approved for chronic lymphocytic leukemia, requires detailed metabolic characterization to support early drug development and selection of appropriate toxicology species. Because drug metabolism varies across species, an integrated system such as primary hepatocytes containing both Phase I and Phase II enzymes is critical for accurately defining metabolic pathways and identifying potential reactive metabolites. DVB metabolism was investigated using primary hepatocytes from human, monkey, dog, rat, and mouse. Incubated samples were analyzed using high-resolution mass spectrometry (HRMS) to detect and characterize metabolites. Structural elucidation was performed based on MS/MS fragmentation patterns. Mechanistic studies were conducted using a selective aldehyde oxidase (AO) inhibitor to assess the role of AO in DVB metabolism. DVB underwent diverse metabolic transformations, including oxidation, N-dealkylation, N-glucuronidation and glutathione (GSH) conjugation, leading to the identification of 18 putative metabolites. Thirteen metabolites, including several glucuronide and GSH conjugates were newly identified. AO-mediated oxidation on the purine ring emerged as a major pathway and was significantly reduced in the presence of an AO inhibitor, confirming its involvement. Two previously unreported GSH conjugates were also characterized, suggesting potential sites of reactive metabolite formation and associated toxicity risk. Comparative analysis revealed distinct species-dependent metabolic profiles, with both shared and species-specific metabolites identified among human, mouse, rat, dog, and monkey hepatocytes. The present study provides a comprehensive cross-species metabolic profile of DVB, highlighting key pathways and novel metabolites, including those linked to potential toxicity. Mouse hepatocytes are recommended for future toxicological studies.
Plant volatile organic compounds (VOCs) are crucial for communication, defense, pollination, and environmental adaptation, playing a key role in the survival and interaction of plants within ecosystems. However, as an important tree species rich in VOCs, the variation characteristics and influencing factors of VOCs on Phoebe hui W.C. Cheng ex Yen C. Yang remain unclear. In this study, we identified 106 VOCs across branches and leaves, of which 91 and 56 were detected, respectively, with 41 in both tissues. Sesquiterpenoids, olefins, fatty acids and conjugates dominated the VOC profiles of branches and leaves. Branches showed higher accumulation of sesquiterpenoids, fatty acids and conjugates, whereas leaves were enriched in olefins. The VOCs distribution and accumulation were strongly structured by environmental variation, with mean annual precipitation (MAP) and soil organic carbon (SOC) emerging as the primary drivers. Together, these findings elucidate the variation patterns and environmental determinants of VOCs in P. hui, providing a foundation for resource conservation and utilization while informing studies of VOC diversity across Phoebe species.
Central nervous system diseases are among the most challenging to treat, mainly due to the blood-brain barrier, which restricts the entry of most therapeutics into the brain, preventing them from reaching pharmacological concentrations. Moreover, the multifactorial causes of these diseases require targeting diverse key processes. In this context, peptide-drug conjugates represent a promising strategy and offer a multitargeting regimen platform. In this work, we describe the latest developments of peptide-drug conjugates for glioma, Alzheimer's, and Parkinson's diseases, highlighting how conjugating payloads to specific peptides can offer several therapeutic advantages over conventional approaches. Particular emphasis was given to the chemical nature of the conjugation bonds and to the synthetic reactions to underscore the versatility of the methods used.
Melittin, a cationic amphipathic 26-residue peptide from bee venom, displays broad-spectrum antibacterial, antitumor and anti-inflammatory activities, yet severe hemolysis, poor cell selectivity, rapid plasma degradation and high immunogenicity hinder its clinical translation. Structural modification is a vital strategy to overcome its druggability limitations. This review systematically summarizes three mainstream modification approaches of melittin: sequence remodeling, chemical derivatization and conjugate engineering. We illustrate how these strategies tune melittin's conformation, charge and amphiphilicity to lower toxicity and immunogenicity, improve in vivo stability, and enable targeted stimulus-responsive delivery, while unraveling its core functional sites and mechanisms. Current research gaps and future directions including combined modification, multifunctional intelligent conjugates, preclinical safety assessment and scaled production optimization are discussed, providing theoretical support for developing safe, effective melittin-based therapeutics.
UFMylation is an evolutionarily conserved ubiquitin-like modification that covalently conjugates UFM1 to lysine residues of substrates via a sequential E1-E2-E3 enzymatic cascade. UFMylation plays a pivotal role in maintaining cellular homeostasis, and its dysregulation is closely linked to multiple major diseases, including malignant tumors, hematopoietic defects, neurodegenerative disorders, and congenital developmental defects, highlighting its important biological significance. However, few substrates of UFMylation have been reported to date, limiting our deep understanding of the mechanistic functions of this modification. This major bottleneck stems from two major technical limitations: the overwhelming abundance of ribosomal protein L26 (RPL26)-UFM1 conjugates masks signals from low-abundance substrates, and conventional methods rely on cumbersome cotransfection of multiple pathway components with poor efficiency and specificity in UFMylated peptides enrichment. To address these challenges, we have developed an effective and specific experimental protocol for UFMylation detection and large-scale substrate identification. This protocol employs CRISPR-Cas9-mediated gene editing to generate UFSP1/UFSP2 double-knockout (UFSP1KO/UFSP2KO , DKO) HEK293T cells, which completely abrogate de-UFMylation and thus significantly elevate global protein UFMylation levels upon exogenous introduction of mature UFM1-ΔC2. In addition, exogenous co-expression of the E3 ligase core components UFL1 and DDRGK1 can further improve the sensitivity of substrate detection. This protocol enables large-scale identification of UFMylation substrates with modification sites via high-efficiency enrichment with the K-ε-VG antibody and LC-MS/MS analysis. Key features • Employs UFSP1/UFSP2 DKO HEK293T cells with exogenous mature UFM1-ΔC2 to enhance UFMylation. • Simplified transfection via single-factor assays using UFM1-ΔC2, UFL1, and DDRGK1. • Combines K-ε-VG antibody enrichment with LC-MS/MS for large-scale substrate identification. • Verifies UFMylation sites via site-directed mutagenesis and UFSP2-mediated de-UFMylation.
Polymer dielectrics exhibit significant advantages in dielectric capacitors due to their high breakdown strength, thermal stability, and excellent processability. However, polyetherimide (PEI) exhibit a significant increase in conduction loss at elevated temperatures due to a strong intramolecular charge transfer effect, severely limiting energy storage performance. This work proposes a design strategy based on molecular structural regulation to suppress conduction loss. Functional diamine units are introduced into the PEI backbone to construct local state traps, while regulating the suppression of charge transport by local hole traps and local large conjugated dihedral angle. The results demonstrate that PEI copolymer films with 4,4'-Oxydianiline (ODA) can achieve optimal regulation between local hole traps and local large conjugated dihedral angle, thereby introducing the deepest local state traps and significantly suppressing charge transport. At 200 °C, PEI-ODA film exhibits an exceptional discharge energy density of 3.82 J/cm3 with an efficiency exceeding 90%, while maintaining high reliability of 50 000 cycles. This research presents a molecular design strategy for high-temperature applications, providing significant insights for the development of high-temperature polymer dielectric for high-power electronic systems.