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学者姓名：李金宇
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Abstract ：
The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (& sdot;OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc ), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metalcoordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.
Keyword ：
Chemodynamical therapy Chemodynamical therapy Ferroptosis Ferroptosis Immunotherapy Immunotherapy Metal -coordinated nanoplatform Metal -coordinated nanoplatform Synergistic chemotherapy Synergistic chemotherapy
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| GB/T 7714 | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu et al. Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis [J]. | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 : 257-276 . |
| MLA | Zhao, Rui-Rui et al. "Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis" . | JOURNAL OF COLLOID AND INTERFACE SCIENCE 660 (2024) : 257-276 . |
| APA | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu , Lu, Yu-sheng , Shao, Jing -Wei . Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis . | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 , 257-276 . |
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Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD+)-bound SPARSA with and without nucleic acids at resolutions of 3.1 angstrom and 3.6 angstrom, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD+ binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD+ hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system. Short prokaryotic Argonaute and Sir2 proteins function as an antivirus system. Here the authors describe structures of SPARSA (a heterodimer of Sir2-APAZ and prokaryotic Argonaute) with and without template DNA and guide RNA, providing structural basis of its assembly and activation by the recognition of the invading virus.
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| GB/T 7714 | Zhen, Xiangkai , Xu, Xiaolong , Ye, Le et al. Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system [J]. | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
| MLA | Zhen, Xiangkai et al. "Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system" . | NATURE COMMUNICATIONS 15 . 1 (2024) . |
| APA | Zhen, Xiangkai , Xu, Xiaolong , Ye, Le , Xie, Song , Huang, Zhijie , Yang, Sheng et al. Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system . | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
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The transport behaviors of aqueous solution in two-dimensional (2D) nanomaterial-based separation membranes are correlated with the structure of the nanoconfined geometry. However, little is known about the impact of asymmetric structures on the transport behavior of aqueous solutions in membranes. In this work, we use molecular dynamics (MD) simulations to investigate the transport behaviors of aqueous solution in non-parallel stacked graphitic carbon nitride (g-C3N4) nanochannels. Interestingly, the non-parallel stacking of g-C3N4 could lead to the local aggregation of water, resulting in an inhomogeneous density distribution within the nanochannel. The high-density region in g-C3N4 nanochannel significantly disrupted the continuum fluid of water. Moreover, the inhomogeneous density distribution of water could impede ion transport in the non-parallel g-C3N4 nanochannel. It was found that ions cannot maintain compact hydration structures in the high-density region. This work reveals the unique properties of slightly tilted membrane structures, providing novel perspective for the design of next-generation nanofluidic devices.
Keyword ：
Desalination Desalination Graphitic carbon nitride Graphitic carbon nitride Inhomogeneous confined structure Inhomogeneous confined structure Molecular dynamics Molecular dynamics Two-dimensional nanochannel Two-dimensional nanochannel
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| GB/T 7714 | Liu, Yichang , Zou, Yujin , Zhu, Hao et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study [J]. | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
| MLA | Liu, Yichang et al. "Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study" . | JOURNAL OF MOLECULAR LIQUIDS 396 (2024) . |
| APA | Liu, Yichang , Zou, Yujin , Zhu, Hao , Xie, Song , Wu, Juhong , Li, Jinlong et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study . | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
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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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Proper chromosome segregation during cell division relies on the timely dissolution of chromosome cohesion. Separase (EC 3.4.22.49), a cysteine protease, plays a critical role in mitosis by cleaving the kleisin subunit of cohesin, thereby presenting a promising target for cancer therapy. However, challenges in isolating active human separase suitable for high-throughput screening have limited the identification of effective inhibitors. Here, we conducted a high-throughput screening of small-molecule inhibitors using the protease domain of Chaetomium thermophilum separase (ctSPD), which not only shares significant sequence similarity with human separase but is also readily available. After conducting a primary screening of a library containing 9,172 compounds and subsequent validation using human separase, we identified walrycin B and its analogs, toxoflavin, 3-methyltoxoflavin, and 3-phenyltoxoflavin, as potent inhibitors of human separase. Subsequent microscale thermophoresis assays and molecular dynamics simulations revealed that walrycin B binds to the active site of separase and competes with substrates for binding. Additionally, cell-based studies showed that walrycin B and its analogs effectively induce cell cycle arrest at the M phase, activate apoptosis, and ultimately lead to cell death in mitosis. Finally, in a mouse xenograft model, walrycin B exhibited significant antitumor efficacy with minimal side effects. Together, these findings highlight the therapeutic potential of walrycin B for cancer treatment and its utility as a chemical tool in future studies involving separase. © 2024 Elsevier Inc.
Keyword ：
Anticancer Anticancer Inhibitor Inhibitor Separase Separase Toxoflavin Toxoflavin Walrycin B Walrycin B
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| GB/T 7714 | Zhu, Q. , Du, L. , Wu, J. et al. Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model [J]. | Biochemical Pharmacology , 2024 , 229 . |
| MLA | Zhu, Q. et al. "Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model" . | Biochemical Pharmacology 229 (2024) . |
| APA | Zhu, Q. , Du, L. , Wu, J. , Li, J. , Lin, Z. . Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model . | Biochemical Pharmacology , 2024 , 229 . |
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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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The lamellar graphitic carbon nitride (g-C3N4) membranes with controllable interlayer thickness could have promising separation performance for desalination. Understanding the molecular basis of the transport behavior of water and ions through well-defined g-C3N4 nanochannels is essential for the design of novel desalination membranes. Herein, we performed non-equilibrium molecular dynamics (MD) simulations to investigate the transport mechanisms of water molecules and ions through g-C3N4 nanochannels with various thicknesses. The confinement effect of the nanochannel could impact the water density distribution between the g-C3N4 nano -sheets. Meanwhile, owing to the strong adsorption effect of g-C3N4 nanosheets, the interfacial water layer and the middle water layer in nanochannels featured with distinct transport behaviors. This water conduction behavior is different from that of graphene nanochannels. For desalination, the MD simulations showed that the g-C3N4 nanochannel could entirely reject the ions when the channel thickness was smaller than 1.0 nm. Additionally, the migration behavior of hydrated ions was correlated with the water structures in g-C3N4 nanochannels. This work not only improved the understanding of the molecular transport mechanism of water molecules and ions in the g-C3N4 nanochannel, but also provided useful guidelines for designing next-generation desalination membranes.
Keyword ：
Desalination Desalination Graphitic carbon nitride Graphitic carbon nitride Molecular dynamics Molecular dynamics Nanochannel Nanochannel Water layer structure Water layer structure
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| GB/T 7714 | Liu, Yichang , Xie, Song , Wu, Juhong et al. Revealing the confinement effects of graphitic carbon nitride nanochannels on the water desalination performance [J]. | SEPARATION AND PURIFICATION TECHNOLOGY , 2023 , 314 . |
| MLA | Liu, Yichang et al. "Revealing the confinement effects of graphitic carbon nitride nanochannels on the water desalination performance" . | SEPARATION AND PURIFICATION TECHNOLOGY 314 (2023) . |
| APA | Liu, Yichang , Xie, Song , Wu, Juhong , Jiang, Lizhi , Liu, Lin , Li, Jinyu . Revealing the confinement effects of graphitic carbon nitride nanochannels on the water desalination performance . | SEPARATION AND PURIFICATION TECHNOLOGY , 2023 , 314 . |
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The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1-MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (-9.8 & PLUSMN; 0.3 kcal/mol) and MC5 (-9.6 & PLUSMN; 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (-8.9 & PLUSMN; 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19.Communicated by Ramaswamy H. Sarma
Keyword ：
COVID-19 COVID-19 inhibitor inhibitor macrodomain macrodomain MD simulation MD simulation metadynamics metadynamics SARS-CoV-2 SARS-CoV-2
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| GB/T 7714 | Xie, Song , Cao, Shoujing , Wu, Juhong et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 [J]. | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS , 2023 , 42 (10) : 5229-5237 . |
| MLA | Xie, Song et al. "In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1" . | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS 42 . 10 (2023) : 5229-5237 . |
| APA | Xie, Song , Cao, Shoujing , Wu, Juhong , Xie, Zhinuo , Liu, Yu-Tsen , Fu, Wei et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 . | JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS , 2023 , 42 (10) , 5229-5237 . |
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The physicochemical differences between DNA and other molecules pose a challenge to the construction of DNA based nanostructures. Herein, we propose a straightforward approach for preparing multifunctional DNA-based nanospheres through direct self-assembly of 2'-fluoro-substituted single-stranded DNA (2'F-DNA) with various small molecules. Molecular dynamics simulation revealed that 2'F substitution in DNA can cause the repulsion of adjacent PO(4)(3-)group, leading to local stretching of the DNA structure. Moreover, 2'F substituent induced the regular polarization of H2O nearby F to form the hydration layer, which interrupts inherent interactions among bases. In this way, the bases of 2'F-DNA chain have fewer constraints and more flexibility in conformation, facilitating their non-covalent interactions with other molecules and enhancing the self-assembly capacity of 2'F-DNA. Consequently, 2'F-DNA can bind to more molecules, tending to spontaneously form hybrid DNA nano spheres. Following this approach, a chemo-gene therapy 2'F-DNA/doxorubicin model was designed, showing the significant synergistic anti-tumor therapeutic efficacy. Taken together, this study provides an expandable approach for constructing engineering hybrid nanospheres using DNA and other small molecules, which holds great potential for further biological applications.
Keyword ：
2'F-DNA 2'F-DNA Chemo-gene therapy Chemo-gene therapy Dynamics simulation Dynamics simulation Self-assembly Self-assembly
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| GB/T 7714 | Wang, Haihui , Jiang, Yifan , Liu, Yichang et al. 20.625pt'0.625pt-Fluoro-substituted DNA-induced self-assembly strategy for engineering hybrid nanospheres [J]. | CHEMICAL ENGINEERING JOURNAL , 2023 , 471 . |
| MLA | Wang, Haihui et al. "20.625pt'0.625pt-Fluoro-substituted DNA-induced self-assembly strategy for engineering hybrid nanospheres" . | CHEMICAL ENGINEERING JOURNAL 471 (2023) . |
| APA | Wang, Haihui , Jiang, Yifan , Liu, Yichang , Zhu, Xiaohui , Liu, Yongfei , Chen, Minle et al. 20.625pt'0.625pt-Fluoro-substituted DNA-induced self-assembly strategy for engineering hybrid nanospheres . | CHEMICAL ENGINEERING JOURNAL , 2023 , 471 . |
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Antimicrobial peptides (AMPs) exert their biological functions by perturbation with cellular membrane. Conjugation of AMPs with photosensitizer (PS) is a promising strategy for enhancing the efficacy and reducing systemic toxicity of AMPs. However, it is still elusive how the conjugated PS impacts the perturbation of AMPs on cell membrane from molecular level. Here, we addressed this issue by a multiscale computational strategy on pyropheophorbide-a (PPA) conjugated K6L9 (PPA-K6L9), a PS-AMP conjugate developed by us previously. Our atomistic molecular dynamics (MD) simulations revealed that the porphyrin moiety of PPA enhanced the stability of the conjugate in a lipid bilayer membrane model. Moreover, such moiety also maintained the amphipathic structure of K6L9, which is crucial for membrane pore formation. Coarse-grained MD simulations further showed that the conjugates aggregated in membrane environment and formed more stable toroidal pores with respect to K6L9 alone, suggesting the conjugation of PPA may enhance the membrane-disruption activity of K6L9. Consistent with this, our cellular experiments confirmed that PPA-K6L9 was more toxic to 4 T1 tumor cells than K6L9. This study provides insights into the mechanism by which PS-AMP conjugates disrupt cellular membranes and could aid in the design of more potent AMP conjugates.
Keyword ：
Antimicrobial peptides Antimicrobial peptides Lipid bilayer Lipid bilayer Multiscale molecular simulation Multiscale molecular simulation Photosensitizer-peptide conjugate Photosensitizer-peptide conjugate
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| GB/T 7714 | Liu, Yichang , Song, Meiru , Wu, Juhong et al. Exploring the mechanism of photosensitizer conjugation on membrane perturbation of antimicrobial peptide: A multiscale molecular simulation study [J]. | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2023 , 247 . |
| MLA | Liu, Yichang et al. "Exploring the mechanism of photosensitizer conjugation on membrane perturbation of antimicrobial peptide: A multiscale molecular simulation study" . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 247 (2023) . |
| APA | Liu, Yichang , Song, Meiru , Wu, Juhong , Xie, Song , Zhou, Yang , Liu, Lin et al. Exploring the mechanism of photosensitizer conjugation on membrane perturbation of antimicrobial peptide: A multiscale molecular simulation study . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2023 , 247 . |
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