JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
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IF 5.895
Hongyan Yang,Lan Wang,Libo Yuan,Heng Du,Boyuan Pan,Kui Lu
A series of hybrid peptides were designed by connecting an antimicrobial peptide Ce(1–8) with a lipopolysaccharide (LPS)-targeting peptide Lf(28–34) via different linkers. Antimicrobial experimental results indicated that linkers play an essential role in the anti-Gram-negative bacterial activity of the hybrid peptides. Among these hybrid peptides, peptide CL5 with dipeptide rigid linker LP exhibited excellent activity and selectivity against Gram-negative bacteria. The minimum inhibitory concentrations of CL5 against the tested Gram-negative bacteria were 4–32 μM, while the toxicity toward HEK-293 cells was relatively low. It was found that the interactions of the peptides with LPS were crucial for peptide activity against Gram-negative bacteria. Antimicrobial mechanistic studies showed that peptide CL5 contributed to the death of Gram-negative bacterial cells by disrupting the integrity of the bacterial membranes. This study revealed the importance of linker selection in the design of hybrid peptides and provides the basis for the further development of antimicrobial peptides.
研究领域:
微生物学
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药物化学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Jingsheng Jiang,Sigang Jian,Feifei Lin,Zhuo Zhang,Qianqian Shen,Guozhang Long,Biyu Yang,Junzhen Lin,Yanfen Fang,Jian Ding,Jia Liu,Yi Chen,Youhong Hu
The ASGR-mediated endocytosis has been successfully applied to the hepatocyte-targeted delivery of therapeutic oligonucleotides via glycoconjugates. However, few studies have explored the conjugated small molecules due to the challenge of cleaving suitable linkers for the release of active small molecules, which is especially different from GalNAc-ONs cleaved by the deoxyribonuclease II in the lysosome. In this study, GalNAc-MMAE conjugates linked by CTSB-cleavable linkers were designed and synthesized. A comprehensive approach revealed that the conjugates were endocytosed by ASGR and subsequently hydrolyzed by CTSB, releasing MMAE. The optimized conjugate with a succinic acid monoamide as the fragment of the linker demonstrated favorable plasma stability, excellent biodistribution, and significant antitumor activities in vivo with weight gain at the effective dose in an orthotopic hepatocellular carcinoma mouse model. This research provides a strategy for developing anti-HCC therapeutic agents using GalNAc drug conjugates with CTSB-cleavable linkers to release active small molecules.
研究领域:
药物化学
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肿瘤学
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肝脏病学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2017
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IF 3.671
Shuqin Xu,Meiling Qiu,Xuanyue Zhang,Jinghua Chen
Heparinase I (Hep I) can efficiently depolymerize heparin and heparin sulfate to oligosaccharides or unsaturated disaccharides, which resulted in loss of physiological function such as blood coagulation. In order to realize the immobilization of Hep I on chitin carriers, we cloned Hep I with the chitin binding domain (ChBD) as a chitin-affinity tag, and the Small Ubiquitin-like MOdifier (SUMO) linker as a solvation enhancer in different fusion sequence. DNA and protein gels suggested that 4 kinds of recombinants were successfully constructed and expressed in Escherichia coli ( E. coli ). And the triple functional heparinases isolated from cell lysate could be efficiently purified by chitin beads. After optimizing fermentation conditions, it gave the specific enzyme activities of 1.88 ± 0.11, 3.69 ± 0.45, 3.44 ± 0.38, and 2.73 ± 0.29 IU/mg total proteins for ChBD-Hep I, ChBD-SUMO-Hep I, SUMO-ChBD-Hep I, and ChBD-Hep I-SUMO, respectively, with unfractionated heparin as substrate. The optimal reaction temperature and pH were determined to be 30 °C and 7.0 for all the fusion enzymes. ChBD-SUMO-Hep I exhibited the maximum half-life (48 min) at 30 °C and best thermo-stability under 15–50 °C. All the fusion enzymes showed broad pH-stability in the range of 5.4–9.0.
研究领域:
生物化学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2019
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IF 4.471
Junhui Shi,Zhengyan Zhao,Zongjun Liu,Ruozheng Wu,You Wang
Background: The design of novel nanoparticles with higher therapeutic efficacy and lower side effects, is still difficult but encouraging in cancer therapy. Specifically, for upconversion nanoparticles (UCNP)-based drug release, a high intensity of NIR light (1.4~5.0 W/cm2) above the maximum permissible exposure (0.33 W/cm2 for 980 nm) is commonly used and severely limits its practical application.Methods: The highly emissive UCNP is first synthesized and then coated with mesoporous silica (MS) shell (UCMS). Next, the surface of UCMS is modified with the thioether (-S-BP) linker, leading to UCMS-S-BP nanoparticles. Finally, after the drug doxorubicin (Dox) is loaded into the pore channels of UCMS, the pore openings are blocked by the β-cyclodextrin (β-CD) gatekeeper through the association with the -S-BP linker (UCMS(Dox)-S-BP@β-CD).Results: Upon 980 nm NIR light irradiation with an ultralow intensity of 0.30 W/cm2, it is found that the loaded Dox can be released through the cleavage of thioether linkers triggering dissociation of β-CD gatekeepers. The in vitro results exhibited significantly therapeutic efficacy with 85.2% of HeLa cells killed in this study.Conclusions: An ultralow-intensity NIR light triggered on-demand drug release system has been developed by employing highly emissive UCNP and photocleavable linker with low bond dissociation energy to avoid the potential photodamage on healthy neighbor cells.
研究领域:
纳米医学
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肿瘤学
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光化学
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DOI
PubMed
高影响因子
Scientific Reports
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2016
·Vol. 6
·期 1
·1-8
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IF 5.228
Lan Jianming,Liu Yingxin,Li Li,Wen Fadi,Wu Fang,Han Zhizhong,Sun Weiming,Li Chunyan,Chen Jinghua
High-sensitivity detection of trace amounts of c-erbB-2 oncogene was reported to be equal to or surpass the ability of CA 15-3 for early diagnosis and/or follow-up recurrent screening of breast cancer. Therefore, in the current study, by using upconversion nanoparticles (UCNPs), rare earth-doped NaYF 4 :Yb 3+ /Er 3+ as the luminescent labels, a upconversion luminescent (UCL) biosensor based on dual-signal amplification of exonuclease III (ExoIII)-assisted target cycles and long-range self-assembly DNA concatamers was developed for the detection of c-erbB-2 oncogene. The proposed biosensor exhibited ultrasensitive detection with limit as low as 40 aM, which may express the potential of being used in trace analysis of c-erbB-2 oncogene and early diagnosis of breast cancer.
研究领域:
生物传感
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癌症诊断
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
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IF 4.845
Xican Zhang,Liangzhu Feng,Ziliang Dong,Xiaoqian Xin,Zhijuan Yang,Dashi Deng,Ernst Wagner,Zhuang Liu,Xiaowen Liu
Combining functional proteins with small molecular drugs into one entity may endow distinct synergistic advantages. However, on account of completely different physicochemical properties of such payloads, co-delivery through systemic administration for therapeutic purpose is challenging. Herein, we designed the protein-drug conjugate HSAP-DC-CAT (human serum albumin/Pt (IV)-dibenzocyclooctyne/chlorin e6-catalase) by modification of CAT and cisplatin pro-drug loaded HSA with pH-sensitive azide linker 3-(azidomethyl)-4-methyl-2,5-furandione (AzMMMan) followed by click chemistry assembly with DC. The dynamic covalent bonds between linker and proteins, on the one hand, can bridge proteins and small molecular drugs in the intermediate state for systemic delivery in the harsh in vivo environment; on the other hand, it can trigger traceless cleavage and release of drugs and proteins with full bioactivity in acidic microenvironment of tumor. The multifunctional HSAP-DC-CAT provides efficient cytosolic transduction in vitro, excellent blood half-lives after systemic administration, and significant antitumor outcome via integrated cisplatin-based chemotherapy and Ce6-based photodynamic therapy enhanced by catalase-induced manipulation of tumor hypoxia microenvironment. This study describes a universal formulation strategy for protein and small molecular drug by a bifunctional linker through amide reaction and click chemistry, with traceless in vivo release of therapeutic units.
研究领域:
药理学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
TALANTA
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2024
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IF 5.6
Xianjing Li,Minlu Cheng,Yiya Wang,Chang Shu,Bingjie Zou,Qinxin Song,Li Ding
Recently, peptide-drug conjugate (PDC) has become the most promising conjugated drug for tumor therapy after antibody-drug conjugate due to stronger tumor penetration capacity and lower immunogenicity . CBP-1018 was a PDC with dual-ligand conjugated to MMAE via a cleavable linker (MC-Val-Cit-PABC) that can be lysed by cathepsins B. In this study, two specific LC-MS/MS methods were developed and validated for the determination of CBP-1018 and its metabolite MMAE in human plasma. To prevent the cleavable MC-Val-Cit-PABC linker from degradation, a protease inhibitor (cOmplete solution) was added to the pre-cooled vacuum tubes and the separated plasma samples. The assays involved the pretreatment of CBP-1018 by protein precipitation with H 2 O-ACN (1:9, v / v ) and the extraction of MMAE by liquid-liquid extraction with ethyl acetate under alkaline condition to eliminate the interference of CBP-1018 on MMAE. The two analytes showed good linearities over the calibration ranges (R 2 ≥ 9980). Both accuracy and precision met the acceptance criteria. The validated methods were successfully applied to the phase I dose-escalation study of CBP-1018 injection in Chinese patients with solid tumors to evaluate the pharmacokinetic properties of CBP-1018 and MMAE. The results showed that CBP-1018 was eliminated immediately after injection and MMAE reached the maximum exposure at approximately 2 h after infusion. The maximum concentration of MMAE did not exceed 20.0 ng/mL, suggesting that the off-target toxicity of CBP-1018 injection was controllable.
研究领域:
药理学
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肿瘤学
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分析化学
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产品关联
DOI
PubMed
高影响因子
Royal Society Open Science
·
2018
·Vol. 5
·期 8
·
IF 2.504
Yuting Yan,Yanwei Cao,Chunsheng Xiao,Yang Li,Xiaoxuan Xiang,Xinhua Guo
Herein, the DNA strands containing 5′-(CGA)n and consecutive guanines are used to construct supramolecular DNA nanostructures that are size-controlled by pH values. Additionally, the introduction of thymine linkers within DNA nanostructures is necessary to maintain the stability of long-sized nanostructures. This work also demonstrates a method for accurately building DNA nanostructures.
研究领域:
纳米技术
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分子生物学
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超分子化学
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DOI
PubMed
高影响因子
CHEMISTRY OF NATURAL COMPOUNDS
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2025
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IF 0.9
Popov S. A.,Qi Z.,Yang G.,Wang C.,Semenova M. D.,Shpatov A. V.,Shults E. E.
New conjugates of lupane triterpenoids bound through a 1,2,3-triazole linker with gallate derivatives were prepared via Cu-catalyzed cycloaddition reactions of [3 β ,28-diacetoxy-20(29)-lupen-30-yl]azide and 3 β -acetoxylup-20(29)-en-30-azido-28-oic acid with gallate derivatives with propargyl substituents in various positions. Conjugate 4 based on betulin with a modified gallate substituent containing a dioxolane moiety possessed potent antioxidant properties and anti-inflammatory activity (suppression of NO hyperexpression).
研究领域:
有机化学
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药理学
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合成化学
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产品关联
DOI
高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY
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2023
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IF 4.3
Shiliang Zhu,Ke Li,Shuai Qin,Jianguo Lin,Ling Qiu
Traditional photodynamic therapy (PDT) suffers from poor tissue penetration due to using external light as excitation source. Cerenkov radiation (CR) from radionuclides can serve as an internal light source to activate photosensitizers inside lesion tissues. Using CR instead of external light in PDT is thought to be an effective way to overcome the shortcoming of traditional PDT. However, the weakness of CR emission limits the outcomes of CR-induced PDT (CR-PDT). We anticipated that CR-induced combined therapy could effectively enhance the therapeutic outcome of CR-PDT. Herein, a ROS-responsive Chemo-PDT agent ( TTC ) was synthesized by conjugation of tetraphenylporphyrin (photosensitizer) with camptothecin (chemotherapeutic drug) through a ROS-cleavable thioketal linker. Under activation by CR emission from gallium-68 ( 68 Ga), the porphyrin moiety could generate ROS , which then cleaves the thioketal linker to induce the subsequent release of CPT. Using [ 68 Ga]Ga-NOTA-Nb109 as an intracellular CR emitter, in comparison with its non-cleavable analogue ( TUC ) only displaying phototoxicity, TTC exhibited much higher cytotoxicity toward A375-hPD-L1 cells due to its combined effect of PDT and chemotherapy. Our work presents a new strategy to use ROS-responsive Chemo-PDT agent to improve the outcomes of CR-PDT.
研究领域:
放射治疗
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癌症治疗
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核医学
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药物化学
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产品关联
DOI
高影响因子
ANALYTICAL CHEMISTRY
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2025
·
IF 6.7
Songkuan Zhuang,Xiaojun Huang,Muyan Diao,Ruiling Dong,Yueyu Dong,Jun Liu,Yizhen Liu
Current one-pot CRISPR diagnostics necessitate meticulous control of nucleic acid hybridization parameters or extensive modification of CRISPR components to achieve complete enzymatic silencing, a fundamental bottleneck limiting their robustness and generalizability. Here, we resolve this challenge through dynamic crRNA reconfiguration, a paradigm-shifting strategy that exploits the intrinsic structural duality of CRISPR RNA. We present CONVERT (CRISPR One-Pot Nucleic acid detection Via Engineered crRNA Reconfiguration Technology), a universal platform where nontarget intact crRNA acts as a universal suppressor, achieving complete Cas12a inhibition during RPA (recombinase polymerase amplification) by irreversible enzyme sequestration. Target detection is initiated through programmable conversion to split crRNA activators, bypassing sequence-specific design constraints entirely. This crRNA conformational switching mechanism is implemented via photocleavable linker cleavage and subsequent assembly with presupplied truncated crRNA (tcrRNA), activating trans-cleavage signal amplification. Three transformative advances emerge: First, the endogenous crRNA engineering eliminates dependency on exogenous nucleic acid blockers or chemical modifications, reducing optimization costs and time. Second, near-total enzymatic suppression ensures zero cross-talk between amplification and detection phases. Third, the unified workflow enables contamination-resistant operation through spatiotemporal control, requiring no physical partitioning. Validated for Enterocytozoon bieneusi detection, the system demonstrates attomolar sensitivity of 1 aM, 100% diagnostic concordance with qPCR, and absolute specificity against related pathogens. By effectively decoupling CRISPR regulation from sequence-context constraints through rational crRNA structural plasticity, this work establishes a generalized framework for next-generation molecular diagnostics.
研究领域:
分子生物学
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生物工程
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诊断技术
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合成生物学
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核酸扩增
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2018
·
IF 3.095
Yiwen You,Zhiyuan Xu,Yun Chen
HER2-positive breast cancer correlates with more aggressive tumor growth, a poorer prognosis and reduced overall survival. Currently, trastuzumab (Herceptin), which is an anti-HER2 antibody, is one of the key drugs. There is evidence indicating that conjugation of trastuzumab with chemotherapy drugs, such as doxorubicin (DOX), for multiple targets could be more effective. However, incomplete penetration into tumors has been noted for those conjugates. Compared to an antibody, peptides may represent an attractive alternative. For HER2, a similar potency has been observed for a 12-amino-acid anti-HER2 peptide mimetic YCDGFYACYMDV-NH2 (AHNP, disulfide-bridged) and full-length trastuzumab. Thus, a peptide, GPLGLAGDDYCDGFYACYMDV-NH2, which consists of AHNP and an MMP-2 cleavable linker GPLGLAGDD, was first designed, followed by conjugation with DOX via a glycine residue at the N-terminus to form a novel DOX-peptide conjugate MAHNP-DOX. Using HER2-positive human breast cancer cells BT474 and SKBR3 as in vitro model systems and nude mice with BT474 xenografts as an in vivo model, this conjugate was comprehensively characterized, and its efficacy was evaluated and compared with that of free DOX. As a result, MAHNP-DOX demonstrated a much lower in vitro IC50, and its in vivo extent of inhibition in mice was more evident. During this process, enzymatic cleavage of MAHNP-DOX is critical for its activation and cellular uptake. In addition, a synergistic response was observed after the combination of DOX and AHNP. This effect was probably due to the involvement of AHNP in the PI3K–AKT signaling pathway, which can be largely activated by DOX and leads to anti-apoptotic signals.
研究领域:
肿瘤学
·
药学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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