CHEMISTRY OF MATERIALS
·
2025
·
IF 7
Jia Kong,Jiaxing Zhang,Yirui Zhang,Huanxin Xue,Xin Guo,Nan Wang,Ziyi Gao,Menghuan Sun,Yinqiang Xia,Yuefei Wang,Hao Ren,Peng Yang,Man Shing Wong
Amyloid β (Aβ) aggregates are a neuropathological hallmark of Alzheimer’s disease (AD). Despite being a prime therapeutic target, past Aβ-targeted trials have primarily focused on its hydrophobic core, yielding unsatisfactory results. In this study, we aligned the structural features of Aβ42 filaments and found that the hydrophobic core and C-terminal region show notable similarities, and the N-terminal region exhibits considerable disorder. Through residue substitution studies, we identified the His13-His14 motif at the disorder–order boundary as particularly effective in mitigating Aβ42’s fibrillation pathway and neurotoxicity, alongside the Phe19-Phe20 hydrophobic core, presenting a promising target for therapeutic intervention. We then designed a series of peptide mimetics based on these Aβ features. Among them, peptide mimetic III, with the sequence of Phe-His-His, exhibited an assembly of antiparallel β-sheet structures primarily driven by hydrogen bonding, showcasing favorable rheological properties and biosafety. Interestingly, mimetic III predominantly patches the N-terminal region of Aβ42 fibrils through hydrogen bond-dominated interactions, effectively modulating aggregation and neurotoxicity in a “like-interacts-with-like” manner. Furthermore, mimetic III eliminates the risk of Aβ42 aggregating into neurotoxic intermediates, rescuing both human and mouse-derived neuronal cells from Aβ42-induced toxicity. Our study demonstrated that peptide mimetics targeting the N-terminal region of Aβ42 is a promising alternative for modulating amyloidosis-related neurotoxicity.
研究领域:
神经生物学
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分子药理学
·
蛋白质聚集疾病
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转化医学
·
神经退行性疾病
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DOI
PubMed
高影响因子
mAbs
·
2018
·
IF 5.165
De-zhi Li,Bing-nan Han,Rui Wei,Gui-yang Yao,Zhizhen Chen,Jie Liu,Terence C.W. Poon,Wu Su,Zhongyu Zhu,Dimiter S. Dimitrov,Qi Zhao
Site-specific conjugation of small molecules to antibody molecules is a promising strategy for generation of antibody-drug conjugates. In this report, we describe the successful synthesis of a novel bifunctional molecule, 6-(azidomethyl)-2-pyridinecarboxyaldehyde (6-AM-2-PCA), which was used for conjugation of small molecules to peptides and antibodies. We demonstrated that 6-AM-2-PCA selectively reacted with N-terminal amino groups of peptides and antibodies. In addition, the azide group of 6-AM-2-PCA enabled copper-free click chemistry coupling with dibenzocyclooctyne-containing reagents. Bifunctional 6-AM-2-PCA mediated site-specific conjugation without requiring genetic engineering of peptides or antibodies. A key advantage of 6-AM-2-PCA as a conjugation reagent is its ability to modify proteins in a single step under physiological conditions that are sufficiently moderate to retain protein function. Therefore, this new click chemistry-based method could be a useful complement to other conjugation methods.
研究领域:
化学
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生物化学
·
药学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2023
·
IF 4.8
Jianchao Zhang,Caibing Ma,Yongjun Yu,Chaowei Liu,Lijing Fang,Hai Rao
Proteolysis-targeting chimera (PROTAC) that specifically targets harmful proteins for destruction by hijacking the ubiquitin-proteasome system (UPS) is emerging as a potent anti-cancer strategy. How to efficiently modulate the target degradation remains a challenging issue. In this study, we employ a single amino acid-based PROTAC, which uses the shortest degradation signal sequence as the ligand of the N-end rule E3 ubiquitin ligases to degrade the fusion protein BCR-ABL, an oncogenic kinase that drives the progression of chronic myeloid leukemia (CML). We find that the reduction level of BCR-ABL can be easily adjusted by substituting different amino acids. Furthermore, a single PEG linker is found to achieve the best proteolytic effect. Our efforts have resulted in effective degradation of BCR-ABL protein by the N-end rule pathway and efficient growth inhibition of K562 cells expressing BCR-ABL in vitro , and blunted tumor growth in a K562 xenograft tumor model in vivo . The PROTAC presented has unique advantages including lower effective concentration, smaller molecular size and modular degradation rate. Demonstrating the efficacy of the N-end rule-based PROTACs in vitro and in vivo , our study further expands the limited degradation pathways currently available for PROTACs in vivo and is easily adapted for broader applications in targeted protein degradation.
研究领域:
肿瘤学
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分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOTECHNOLOGY
·
2020
·
IF 3.503
Shi-Yu Zhang,Ze-Wang Guo,Xiao-Ling Wu,Xiao-Yang Ou,Min-Hua Zong,Wen-Yong Lou
Cold-adapted pullulanase with high catalytic activity and stability is of special interest for its wide application in cold starch hydrolysis, but few pullulanases displaying excellent characteristics at ambient temperature and acidic pH have hitherto been reported. Here, a novel pullulanase from Bacillus methanolicus PB1 was successfully expressed in Escherichia coli BL21 (DE3) and determined to be a cold-adapted type I pullulanase (PulPB1) with maximum activity at 50 °C and pH 5.5. The recombinant PulPB1 showed great stability, its half-life at 50 °C was 137 h. PulPB1 can efficiently hydrolyze pullulan and amylopectin, with activities of 292 and 184 U/mg at 50 °C and pH 5.5, respectively. Moreover, the N-terminal domain of PulPB1 was found to significantly affect the enzymatic performance. Following truncation of the N-terminal domain, the activity towards pullulan decreased markedly from 292 to 141 U/mg and the half-life at 50 °C decreased from 137 to 10 h. Compared to the hydrolysis system with amyloglucosidase alone, the catalytic efficiency showed a 2.4-fold increase on combining PulPB1 with amyloglucosidase for amylopectin hydrolysis at 40 °C. This demonstrates that PulPB1 is promising for development as a superior candidate for cold amylopectin hydrolysis.
研究领域:
生物化学
·
微生物学
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酶学
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生物技术
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产品关联
DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2024
·
IF 4.3
Libo Yuan,Ke Wang,Lei Lei,Dongxin Zhao,Hongyan Yang,Yuan Fang,Kui Lu
A series of Andricin B derivatives were designed and synthesized using fatty acid modification at N-terminus of the antimicrobial peptides. The hydrophobicity of Andricin B was altered through fatty acid modification, and the bioactivity was investigated. The interaction between Andricin B and its derivatives with DNA was measured using multi-spectroscopy. Spectroscopic analysis revealed that Andricin B and its derivatives can interact with ct-DNA and G-quadruplexes DNA, and the interaction related with the length of fatty acid chain. Antimicrobial activity tests showed a significant increase using peptides with 8–10 carbons fatty acid chain. C10-Andricin B exhibited the highest antimicrobial activity, with up to a 16-fold enhancement compared to the original peptide Andricin B. Meanwhile, the protease hydrolysis stability test showed that fatty acid modification improved the stability of Andricin B against protease. Scanning electron microscopy results distinctly showed that C8-Andricin B could rupture the cell wall of bacteria. All results indicated that fatty acid modification peptides are an effective strategy for enhancing activity and stability of antimicrobial peptides. This research provides valuable insights for further research on antimicrobial peptides.
研究领域:
生物化学
·
药物化学
·
微生物学
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产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2020
·
IF 5.893
Yongzhou Yu,Zuxiao Yang,Baohua Jin,Xia Qin,Xiaoque Zhu,Jiahui Sun,Lifang Huo,Ri Wang,Yongyun Shi,Zhanfeng Jia,Yun Stone Shi,Shifeng Chu,Dezhi Kong,Wei Zhang
Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Falin He,Huijian Shi,Shaoyang Hu,Rutao Liu
Currently, the binding of iron-binding protein transferrin (TF) with NPs and their interaction mechanisms have not been completely elucidated yet. Here, we probed the conformation-dependent release of Fe ions from TF induced by nano-sized polystyrene plastics (PS-NPs) using dialysis, ICP-MS, multi-spectroscopic techniques, and computational simulation. The results showed that the release of free Fe ions from TF was activated after PS-NPs binding, which displayed a clear dose-effect correlation. PS-NPs binding can induce the unfolding and loosening of polypeptide chain and backbone of TF. Alongside this we found that the TF secondary structure was destroyed, thereby causing TF protein misfolding and denaturation. In parallel, PS-NPs interacted with the chromophores , resulting in the occurrence of fluorescence sensitization effects and the disruption of the surrounding micro-environment of aromatic amino acids . Also, the binding of PS-NPs induced the formation of new aggregates in the PS-NPs-TF system. Further simulations indicated that PS-NPs exhibited a preference for binding to the hinge region that connects the C-lobe and N-lobe, which is responsible for the Fe ions release and structural alterations of TF. This finding provides a new understanding about the regulation of the release of Fe ions of iron-loaded TF through NPs-induced conformational and structural changes.
研究领域:
生物化学
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分子生物学
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纳米技术
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蛋白质化学
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产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2019
·Vol. 11
·期 46
·5919-5928
·
IF 2.378
Nasibeh Saeedzadeh Amiri,Mohammad-Reza Milani-Hosseini
A facile and environmental-friendly strategy was used to prepare ratiometric fluorescence sensor-modified mesoporous-structured epitope-imprinted polymer (QDs@SiO2@EMSiO2) for highly sensitive and selective determination of cytochrome c (Cyt c), using Cu-doped ZnS QDs and Mn-doped ZnS QDs as fluorescent dyes. In this sensor, C-terminal and N-terminal nonapeptides were employed as the template molecules, and C18MIMCl was utilized as a template for mesoporous silica. APTES and PTESMIC were utilized as functional monomers and TEOS was applied as the cross-linker. The as-prepared fluorescence sensor displayed great selectivity and sensitivity by merging ratiometric fluorescence methodology with mesoporous silica materials to create one system. The composite was employed for the recognition of Cyt c, which displayed good linearity in the range from 0.4 nM to 200.0 nM with a detection limit as low as 0.15 nM, which was much lower than those of non-mesoporous and single emission composites. The sensor also exhibited outstanding applicability in complex matrices, which enabled its employment for Cyt c tracing in human serum samples without any pretreatment.
研究领域:
分析化学
·
材料科学
·
生物传感器
·
生物技术
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）