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学者姓名：袁彩
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Aims Alteplase is a cornerstone thrombolytic agent in clinical practice but presents a potential bleeding risk. Stroke patients need pre-screening to exclude haemorrhagic stroke before using alteplase. In this study, we develop a new thrombolytic agent citPA5, characterized by an enhanced safety profile and minimal bleeding tendency.Methods and results A clot lysis agent, named citPA5, is developed based on rtPA with point mutations to completely suppress its proteolytic activity in the absence of fibrin. In the presence of fibrin, citPA5 exhibited significantly higher fibrinolytic activity (a 15.8-fold increase of kcat/Km). Furthermore, citPA5 showed resistance to endogenous fibrinolysis inhibitor, PAI-1, resulting in enhanced potency. In a series of safety evaluation experiments, including thrombelastography assay, mice tail bleeding assay, and a murine intracerebral haemorrhage (ICH) model, citPA5 did not cause systemic bleeding or worsen ICH compared with alteplase. This highlights the low risk of bleeding associated with citPA5. Finally, we found that citPA5 effectively improved cerebral blood flow and reduced infarct volume in a carotid embolism-induced stroke model.Conclusion This clot lysis agent, citPA5, not only exhibits a low risk of bleeding but also demonstrates highly effective thrombolysis capabilities. As a result, citPA5 shows great potential for administration prior to the classification of stroke types, making it possible for use in ambulances at the onset of stroke when symptoms are identified. The findings presented in this study also suggest that this strategy could be applied to develop a new generation of fibrinolytic drugs that offer greater safety and specificity in targeting fibrin. Graphical Abstract
Keyword ：
Enhanced tPA potency Enhanced tPA potency Ischaemic stroke Ischaemic stroke Low bleeding risk Low bleeding risk Thrombolytic therapy Thrombolytic therapy
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| GB/T 7714 | Chen, Shanli , Fang, Sudan , Zhou, Yang et al. A low bleeding risk thrombolytic agent: citPA5 [J]. | CARDIOVASCULAR RESEARCH , 2024 , 120 (10) : 1191-1201 . |
| MLA | Chen, Shanli et al. "A low bleeding risk thrombolytic agent: citPA5" . | CARDIOVASCULAR RESEARCH 120 . 10 (2024) : 1191-1201 . |
| APA | Chen, Shanli , Fang, Sudan , Zhou, Yang , Huang, Zhiwei , Yu, Shujuan , Chen, Dan et al. A low bleeding risk thrombolytic agent: citPA5 . | CARDIOVASCULAR RESEARCH , 2024 , 120 (10) , 1191-1201 . |
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Bacterial infections of plants are widespread and highly virulent, causing serious economic losses in agricultural production worldwide. These infections become particularly prevalent during rainy weather, characterized by high humidity and low light intensity (about 2-10% of a sunny day). Here we identified a class of photosensitizers that were effective in inhibiting plant bacterial infections under rainy weather with dim light. One of these compounds, compound 1, demonstrated exceptional efficacy by eliminating more than 4 logs (99.99%) of either Xanthomonas perforans or Xanthomonas citri subsp. citri (Xcc) strain at a concentration of 6.25 mu M under rainy weather conditions with a light exposure of 28.51 J/cm2. For Clavibacter michiganensis (Cm), compound 1 demonstrated a comparable bactericidal effect at a lower concentration of 3.13 mu M. Furthermore, compound 1 was effective in controlling plant leaf infections during rainy weather. Moreover, compound 1 exhibited a potent inhibitory effect on the biofilms pertinent to tomato spot disease and citrus canker under natural illumination on rainy days. Additionally, compound 1 displayed remarkable resilience to rain-wash on plant leaves, retaining 41.20% of its initial concentration following exposure to three simulated rain events. These findings provide a new strategy for plant pathogen disease management highlight its feasibility even during rainy weather.
Keyword ：
Biofilm Biofilm Photosensitizer Photosensitizer Plant bacterial infection Plant bacterial infection Rain fastness Rain fastness
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| GB/T 7714 | Wang, Guodong , Li, Jiahui , Zhang, Wei et al. A class of photosensitizer highly effective to control bacterial infection in plants even on rainy days with dim light [J]. | DYES AND PIGMENTS , 2024 , 225 . |
| MLA | Wang, Guodong et al. "A class of photosensitizer highly effective to control bacterial infection in plants even on rainy days with dim light" . | DYES AND PIGMENTS 225 (2024) . |
| APA | Wang, Guodong , Li, Jiahui , Zhang, Wei , Jiang, Libin , Mai, Yuhan , Chen, Jingyi et al. A class of photosensitizer highly effective to control bacterial infection in plants even on rainy days with dim light . | DYES AND PIGMENTS , 2024 , 225 . |
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In the type III CRISPR system, cyclic oligoadenylate (cOA) molecules act as second messengers, activating various promiscuous ancillary nucleases that indiscriminately degrade host and viral DNA/RNA. Conversely, ring nucleases, by specifically cleaving cOA molecules, function as off-switches to protect host cells from dormancy or death, and allow viruses to counteract immune responses. The fusion protein Csx1-Crn2, combining host ribonuclease with viral ring nuclease, represents a unique self-limiting ribonuclease family. Here, we describe the structures of Csx1-Crn2 from the organism of Marinitoga sp., in both its full-length and truncated forms, as well as in complex with cA4. We show that Csx1-Crn2 operates as a homo-tetramer, a configuration crucial for preserving the structural integrity of the HEPN domain and ensuring effective ssRNA cleavage. The binding of cA4 to the CARF domain triggers significant conformational changes across the CARF, HTH, and into the HEPN domains, leading the two R-X4-6-H motifs to form a composite catalytic site. Intriguingly, an acetate ion was found to bind at this composite site by mimicking the scissile phosphate. Further molecular docking analysis reveals that the HEPN domain can accommodate a single ssRNA molecule involving both R-X4-6-H motifs, underscoring the importance of HEPN domain dimerization for its activation. Graphical Abstract
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| GB/T 7714 | Zhang, Danping , Du, Liyang , Gao, Haishan et al. Structural insight into the Csx1-Crn2 fusion self-limiting ribonuclease of type III CRISPR system [J]. | NUCLEIC ACIDS RESEARCH , 2024 , 52 (14) : 8419-8430 . |
| MLA | Zhang, Danping et al. "Structural insight into the Csx1-Crn2 fusion self-limiting ribonuclease of type III CRISPR system" . | NUCLEIC ACIDS RESEARCH 52 . 14 (2024) : 8419-8430 . |
| APA | Zhang, Danping , Du, Liyang , Gao, Haishan , Yuan, Cai , Lin, Zhonghui . Structural insight into the Csx1-Crn2 fusion self-limiting ribonuclease of type III CRISPR system . | NUCLEIC ACIDS RESEARCH , 2024 , 52 (14) , 8419-8430 . |
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Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (12) and L-3-(N-amidino-4-piperidyl)alanine (16), as novel P1 residues in peptide inhibitors. 16 notably enhances affinities across all tested proteases, whereas 12 specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of 12 towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases. © 2024 Elsevier Inc.
Keyword ：
P1 residue P1 residue Peptide inhibitors Peptide inhibitors S1 pocket S1 pocket Serine protease Serine protease Specificity Specificity
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| GB/T 7714 | Lin, H. , Xu, M. , Jiang, L. et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue [J]. | Bioorganic Chemistry , 2024 , 152 . |
| MLA | Lin, H. et al. "Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue" . | Bioorganic Chemistry 152 (2024) . |
| APA | Lin, H. , Xu, M. , Jiang, L. , Yuan, C. , Jiang, C. , Huang, M. et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue . | Bioorganic Chemistry , 2024 , 152 . |
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Human heavy chain ferritin (HFn) protein cage has been explored as a nanocarrier for targeted anticancer drug delivery. Here, we introduced a matrix metalloproteinases (MMPs)-cleavable sequence into the DE loop of HFn, creating an MMP-responsive variant, MR-HFn, for localized and extracellular drug release. The crystal structure of MR-HFn revealed that the addition of the MMPs recognition sequence did not affect the self -assembly of HFn but presented a surface -exposed loop susceptible to MMPs cleavage. Biochemical analysis indicated that this engineered protein cage is responsive to MMPs, enabling the targeted release of encapsulated drugs. To evaluate the therapeutic potential of this engineered protein cage, monosubstituted beta -carboxy phthalocyanine zinc (CPZ), a type of photosensitizer, was loaded inside this protein cage. The prepared CPZ@MR-HFn showed higher uptake and stronger phototoxicity in MMPs overexpressed tumor cells, as well as enhanced penetration into multicellular tumor spheroids compared with its counterpart CPZ@HFn in vitro. In vivo, CPZ@MR-HFn displayed a higher tumor inhibitory rate than CPZ@HFn under illumination. These results indicated that MR-HFn is a promising nanocarrier for anticancer drug delivery and the MMP-responsive strategy here can also be adapted for other stimuli.
Keyword ：
Human heavy chain ferritin Human heavy chain ferritin Localized extracellular release Localized extracellular release Tumor microenvironment responsive Tumor microenvironment responsive
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| GB/T 7714 | Yan, Wen , Li, Hanlin , Ning, Jiamin et al. Engineered protein cages with enhanced extracellular drug release for elevated antitumor efficacy [J]. | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2024 , 267 . |
| MLA | Yan, Wen et al. "Engineered protein cages with enhanced extracellular drug release for elevated antitumor efficacy" . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 267 (2024) . |
| APA | Yan, Wen , Li, Hanlin , Ning, Jiamin , Huang, Shuhao , Jiang, Longguang , Xu, Peng et al. Engineered protein cages with enhanced extracellular drug release for elevated antitumor efficacy . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2024 , 267 . |
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Background: Endothelial hyperpermeability-induced vascular dysfunction is a prevalent and significant characteristic in critical illnesses such as sepsis and other conditions marked by acute systemic inflammation. Platelet endothelial cell adhesion molecule-1 (PECAM-1) and Tie2 serve as transmembrane receptors within endothelial cells (ECs), playing pivotal roles not only in maintaining EC-EC junctions but also in influencing vasculogenesis, vessel homeostasis, and vascular remodeling. Objectives: At present, the molecular basis of the PECAM-1-Tie2 interaction remains inadequately elucidated. In the study, recombinant soluble PECAM-1 (sPECAM-1) and Tie2 (sTie2) were expressed by Drosophila S2 and HEK293 expression systems, respectively. The interactions between sPECAM-1 and sTie2 were investigated using the Surface Plasmon Resonance (SPR) and size-exclusion chromatography methods. An immunofluorescence assay was used to detect the binding of sPECAM-1 and sTie2 on endothelial cells. Results: PECAM-1 was found to bind with sTie2 in a sodium and pH-dependent manner as confirmed by the ELISA, the D5-D6 domains of PECAM-1 might play a crucial role in binding with sTie2. Surface Plasmon Resonance (SPR) results showed that the full length of sPECAM-1 has the strongest binding affinity (KD = 48.4 nM) with sTie2, compared to sPECAM-1-D1-D4 and sPECAM-1-D1-D2. This result is consistent with that in the ELISA. In addition, size-exclusion chromatography demonstrated that sPECAM-1, sTie2, and Ang1 can form a ternary complex. Conclusion: In this study, we determined that sPECAM-1 binds to sTie2 in a pH and sodium-dependent manner. The full length of sPECAM-1 has the strongest binding affinity, and the D5-D6 domains in sPECAM-1 play a crucial role in the interaction between sPECAM-1 and sTie2.
Keyword ：
Angiopoietin-1 Angiopoietin-1 Endothelial cell Endothelial cell PECAM-1 PECAM-1 Protein-protein interaction Protein-protein interaction Tie2 Tie2
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| GB/T 7714 | Li, Hao , Wang, Rui , Xu, Peng et al. Elucidating the molecular basis of PECAM-1 and Tie2 interaction from binding dynamics and complex formation [J]. | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS , 2024 , 735 . |
| MLA | Li, Hao et al. "Elucidating the molecular basis of PECAM-1 and Tie2 interaction from binding dynamics and complex formation" . | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 735 (2024) . |
| APA | Li, Hao , Wang, Rui , Xu, Peng , Yuan, Cai , Huang, Mingdong , Jiang, Longguang . Elucidating the molecular basis of PECAM-1 and Tie2 interaction from binding dynamics and complex formation . | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS , 2024 , 735 . |
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Urokinase plasminogen activator receptor (uPAR) is a key participant in extracellular proteolysis, tissue remodeling and cell motility. uPAR overexpresses in most solid tumors and several hematologic malignancies, but has low levels on normal tissues, thus is advocated as a molecular target for cancer therapy. One of the obstacles for the evaluation of uPAR targeting agents in preclinical study is the species specificity, where targeting agents for human uPAR usually not bind to murine uPAR. Here, we develop a targeting agent that binds to both murine and human uPAR. This targeting agent is genetically fused to human serum albumin, a commonly used drug carrier, and the final construct is named as uPAR targeting carrier (uPARTC). uPARTC binds specifically to uPAR-overexpressing 293T/huPAR and 293T/muPAR as demonstrated by flow cytometry. A cytotoxic compound, celastrol, is embedded into uPARTC non-covalently. The resulting macromolecular complex show effective proliferation inhibition on both murine and human uPAR overexpressing cells, and exhibit potent antitumor efficacy on hepatoma H22-bearing mice. This work demonstrates that uPARTC is a promising tumor targeting drug carrier, which address the species-specificity challenge of uPAR targeting agents and can be used to load other cytotoxic compounds.
Keyword ：
Cancer therapy Cancer therapy Celastrol Celastrol Drug carrier Drug carrier HSA HSA uPAR uPAR
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| GB/T 7714 | Li, Hanlin , Wang, Zhiyou , Yu, Shujuan et al. Albumin-based drug carrier targeting urokinase receptor for cancer therapy [J]. | INTERNATIONAL JOURNAL OF PHARMACEUTICS , 2023 , 634 . |
| MLA | Li, Hanlin et al. "Albumin-based drug carrier targeting urokinase receptor for cancer therapy" . | INTERNATIONAL JOURNAL OF PHARMACEUTICS 634 (2023) . |
| APA | Li, Hanlin , Wang, Zhiyou , Yu, Shujuan , Chen, Shanli , Zhou, Yang , Qu, Yuhan et al. Albumin-based drug carrier targeting urokinase receptor for cancer therapy . | INTERNATIONAL JOURNAL OF PHARMACEUTICS , 2023 , 634 . |
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Diltiazem and glibenclamide are commonly used hypotensive and antidiabetic drugs. This study reports the discovery of the potential antitumor and antimetastatic effects of these two drugs using a structural dynamics-driven virtual screening targeting urokinase receptor (uPAR). Owing to uPAR's high flexibility, currently resolved crystal structures of uPAR, all in ligand-bound states, provide limited representations of its physiological conformation. To improve the accuracy of screening, we performed a long-timescale molecular dynamics simulation and obtained the representative conformations of apo-uPAR as the targets for our screening. Experimentally, we demonstrated that diltiazem and glibenclamide bound uPAR with KD values in the micromolar range. In addition, both compounds effectively suppressed tumor growth and metastasis in a uPAR-dependent manner in vitro and in vivo. This work not only provides two potent uPAR inhibitors but also reports a proof-of-concept study on the potential off-label antitumor and antimetastatic uses of diltiazem and glibenclamide.
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| GB/T 7714 | Zhou, Yang , Song, Meiru , Xie, Daoqing et al. Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor [J]. | JOURNAL OF MEDICINAL CHEMISTRY , 2023 , 66 (8) : 5415-5426 . |
| MLA | Zhou, Yang et al. "Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor" . | JOURNAL OF MEDICINAL CHEMISTRY 66 . 8 (2023) : 5415-5426 . |
| APA | Zhou, Yang , Song, Meiru , Xie, Daoqing , Yan, Shufeng , Xie, Song , Cai, Meiqin et al. Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor . | JOURNAL OF MEDICINAL CHEMISTRY , 2023 , 66 (8) , 5415-5426 . |
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Recombinant tissue-type plasminogen activator (rtPA, or Alteplase) is the first approved thrombolytic drug for acute ischemic stroke, but suffers from a short half-life and poor resistance to plasminogen activator inhibitor (PAI-1), limiting its clinical use. The development of novel thrombolytic agents with improved benefit/risk balance has always been of great significance. In this study, we identified a mutant of serine protease domain of tPA (named AtPAA146V) capable of escaping the inhibition by endogenous PAI-1 with 66-fold increased resistance compared to the wild type tPA. Based on this mutant, we generated a triple fusion AtPA (TriF-AtPA) containing albumin and fibrin binding peptide(FBP). The fusion with albumin effectively prolonged the plasma half-life of AtPA in mice to 144 min, which is much longer than AtPA and did not affect its thrombolytic activity. Furthermore, FBP rendered fibrin specificity of the fusion protein, giving a dissociation constant of similar to 25 +/- 0.9 mu M. In a novel murine carotid embolism-induced stroke (CES) model, i.v. administration of TriF-AtPA promoted vascular recanalization, reduced infarct volume, and mitigated neurobehavioral deficits more significantly compared to AtPA-HSA or Alteplase, showing little bleeding risk. Together, this long-acting PAI-1-resistant thrombolytic agent holds great potential for clinical applications.
Keyword ：
Albumin Albumin Carotid embolism-induced stroke model Carotid embolism-induced stroke model Ischemic stroke Ischemic stroke PAI-1 resistance PAI-1 resistance Thrombolysis Thrombolysis Tissue-type plasminogen activator Tissue-type plasminogen activator
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| GB/T 7714 | Xu, Yanyan , Chen, Dan , Liu, Peiwen et al. A triple fusion tissue-type plasminogen activator (TriF-AtPA) enhanced thrombolysis in carotid embolism-induced stroke model [J]. | INTERNATIONAL JOURNAL OF PHARMACEUTICS , 2023 , 637 . |
| MLA | Xu, Yanyan et al. "A triple fusion tissue-type plasminogen activator (TriF-AtPA) enhanced thrombolysis in carotid embolism-induced stroke model" . | INTERNATIONAL JOURNAL OF PHARMACEUTICS 637 (2023) . |
| APA | Xu, Yanyan , Chen, Dan , Liu, Peiwen , Hu, Yinping , Peng, Shuangzhou , Chen, Shanli et al. A triple fusion tissue-type plasminogen activator (TriF-AtPA) enhanced thrombolysis in carotid embolism-induced stroke model . | INTERNATIONAL JOURNAL OF PHARMACEUTICS , 2023 , 637 . |
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Photodynamic therapy (PDT) is recognized as a powerful method to inactivate cells. However, the photosensitizer (PS), a key component of PDT, has suffered from undesired photobleaching. Photobleaching reduces reactive oxygen species (ROS) yields, leading to the compromise of and even the loss of the photodynamic effect of the PS. Therefore, much effort has been devoted to minimizing photobleaching in order to ensure that there is no loss of photodynamic efficacy. Here, we report that a type of PS aggregate showed neither photobleaching nor photodynamic action. Upon direct contact with bacteria, the PS aggregate was found to fall apart into PS monomers and thus possessed photodynamic inactivation against bacteria. Interestingly, the disassembly of the bound PS aggregate in the presence of bacteria was intensified by illumination, generating more PS monomers and leading to an enhanced antibacterial photodynamic effect. This demonstrated that on a bacterial surface, the PS aggregate photo-inactivated bacteria via PS monomer during irradiation, where the photodynamic efficiency was retained without photobleaching. Further mechanistic studies showed that PS monomers disrupted bacterial membranes and affected the expression of genes related to cell wall synthesis, bacterial membrane integrity, and oxidative stress. The results obtained here are applicable to other types of PSs in PDT.
Keyword ：
photobleaching photobleaching photosensitizer aggregate photosensitizer aggregate photosensitizer monomer photosensitizer monomer photosensitizer (PS) photosensitizer (PS)
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| GB/T 7714 | Liu, Dafeng , Jiang, Longguang , Chen, Jincan et al. Monomer and Oligomer Transition of Zinc Phthalocyanine Is Key for Photobleaching in Photodynamic Therapy [J]. | MOLECULES , 2023 , 28 (12) . |
| MLA | Liu, Dafeng et al. "Monomer and Oligomer Transition of Zinc Phthalocyanine Is Key for Photobleaching in Photodynamic Therapy" . | MOLECULES 28 . 12 (2023) . |
| APA | Liu, Dafeng , Jiang, Longguang , Chen, Jincan , Chen, Zhuo , Yuan, Cai , Lin, Donghai et al. Monomer and Oligomer Transition of Zinc Phthalocyanine Is Key for Photobleaching in Photodynamic Therapy . | MOLECULES , 2023 , 28 (12) . |
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