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学者姓名：李金宇
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Abstract ：
The development of RNA interference (RNAi) therapy offers a potential solution for Alzheimer's disease (AD). However, the brain-blood barrier (BBB) with its selective permeability and pharmacokinetic-related challenges poses restrictions on the delivery of small interfering RNA (siRNA) to the central nervous system (CNS). In this study, we demonstrate that the incorporation of 2 '-fluoro (2 '-F) substitutions and L-carnitine modification facilitates the self-assembly of siRNA through triple interaction, leading to the formation of nanorings, called LCSF-NR. Based on the enhanced cellular uptake and lysosomal escape by 2 '-F substitution and the transport across the BBB promoted by L-carnitine, the nanorings realized the improved brain-targeted delivery of siRNA, both in zebrafish and mice models. Moreover, our findings highlight the therapeutic potential of LCSF-NR formulation in an AD zebrafish model through a synergistic effect of downregulating the beta-site APP cleavage enzyme 1 (BACE1) gene and L-carnitine-mediated neuroprotection, effectively inhibiting pathological processes. Overall, these results suggest that the chemical modification-based siRNA self-assembly strategy enables trans-BBB delivery and presents a concise approach for synergistic therapy of AD.
Keyword ：
Alzheimer's disease Alzheimer's disease blood-brain barrier blood-brain barrier chemical modification chemical modification self-assembly self-assembly siRNA siRNA
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| GB/T 7714 | Jiang, Yifan , Li, Lisha , Fang, Xiao et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease [J]. | SCIENCE CHINA-CHEMISTRY , 2025 . |
| MLA | Jiang, Yifan et al. "Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease" . | SCIENCE CHINA-CHEMISTRY (2025) . |
| APA | Jiang, Yifan , Li, Lisha , Fang, Xiao , Zeng, Tao , Su, Lichao , Liu, Yichang et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease . | SCIENCE CHINA-CHEMISTRY , 2025 . |
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The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met436Arg (M436R) and Ala451Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBDA451D, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1A451D enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1A451D as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.
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| GB/T 7714 | Wang, Rui , Li, Hao , Xie, Zhinuo et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice [J]. | SCIENCE ADVANCES , 2025 , 11 (3) . |
| MLA | Wang, Rui et al. "Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice" . | SCIENCE ADVANCES 11 . 3 (2025) . |
| APA | Wang, Rui , Li, Hao , Xie, Zhinuo , Huang, Meijuan , Xu, Peng , Yuan, Cai et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice . | SCIENCE ADVANCES , 2025 , 11 (3) . |
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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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Sialylation, a critical post-translational modification, regulates glycoprotein structure and function by tuning their molecular heterogeneity. However, characterizing its subtle and dynamic conformational effects at the intact glycoprotein level remains challenging. We introduce a glycoform-resolved unfolding approach based on a high-throughput ion mobility-mass spectrometry (IM-MS) platform. This method integrates high-throughput unfolding with parallel fragmentation, enabling simultaneous analysis of sialylation patterns, stoichiometries, and their impact on conformational stability. Applying this approach to fetuin, we identified distinct sialylation patterns and their differential influence on protein conformation, namely sialylation-induced stabilization during early unfolding and increased flexibility in later unfolding stages. IM-MS-guided molecular dynamics simulations revealed that increased sialylation enhances the initial conformational stability, likely through enhanced electrostatic interactions and hydrogen bonding. These findings highlight the complex interplay between sialylation and protein dynamics and establish glycoform-resolved unfolding IM-MS as a powerful tool for characterizing glycoprotein conformational landscapes. © 2024 The Royal Society of Chemistry.
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| GB/T 7714 | Jia, Y. , Liu, Y. , Wang, Y. et al. Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry [J]. | Chemical Science , 2024 , 15 (35) : 14431-14439 . |
| MLA | Jia, Y. et al. "Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry" . | Chemical Science 15 . 35 (2024) : 14431-14439 . |
| APA | Jia, Y. , Liu, Y. , Wang, Y. , Li, J. , Li, G. . Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry . | Chemical Science , 2024 , 15 (35) , 14431-14439 . |
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The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation. © The Author(s) 2024.
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| GB/T 7714 | Fu, J. , Li, S. , Guan, H. et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms [J]. | Nature Communications , 2024 , 15 (1) . |
| MLA | Fu, J. et al. "Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms" . | Nature Communications 15 . 1 (2024) . |
| APA | Fu, J. , Li, S. , Guan, H. , Li, C. , Zhao, Y.-B. , Chen, T.-T. et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms . | Nature Communications , 2024 , 15 (1) . |
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Abstract ：
The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation. The bacterial pathogen Legionella pneumophila secretes effectors that affect protein ubiquitination within host cells, involving production of phosphoribosyl ubiquitin (PR-Ub). Here, the authors identify additional effectors that convert PR-Ub back into functional ubiquitin, thus maintaining ubiquitin homeostasis in infected cells.
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| GB/T 7714 | Fu, Jiaqi , Li, Siying , Guan, Hongxin et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms [J]. | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
| MLA | Fu, Jiaqi et al. "Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms" . | NATURE COMMUNICATIONS 15 . 1 (2024) . |
| APA | Fu, Jiaqi , Li, Siying , Guan, Hongxin , Li, Chuang , Zhao, Yan-Bo , Chen, Tao-Tao et al. Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms . | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
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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 ± 0.3 kcal/mol) and MC5 (−9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (−8.9 ± 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 | Song Xie , Shoujing Cao , Juhong Wu et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 [J]. | Journal of Biomolecular Structure and Dynamics , 2024 , 42 (10) : 5229-5237 . |
| MLA | Song Xie et al. "In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1" . | Journal of Biomolecular Structure and Dynamics 42 . 10 (2024) : 5229-5237 . |
| APA | Song Xie , Shoujing Cao , Juhong Wu , Zhinuo Xie , Yu-Tsen Liu , Wei Fu et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 . | Journal of Biomolecular Structure and Dynamics , 2024 , 42 (10) , 5229-5237 . |
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The combination of infrared spectroscopy (IR) and ion mobility mass spectrometry (IM-MS) has revealed that protein secondary structures are retained upon transformation from aqueous solution to the gas phase under gentle conditions. Yet the details about where and how these structural elements are embedded in the gas phase remain elusive. In this study, we employ long time scale molecular dynamics (MD) simulations to examine the extent to which proteins retain their solution structures and the impact of protonation state on the stability of secondary structures in the gas phase. Our investigation focuses on two well-studied proteins, myoglobin and beta-lactoglobulin, representing typical helical and beta-sheet proteins, respectively. Our simulations accurately reproduce the experimental collision cross section (CCS) data measured by IM-MS. Based on accurately reproducing previous experimental collision cross section data and dominant secondary structural species obtained from IM-MS and IR, we confirm that both proteins largely retain their native secondary structural components upon passing from aqueous solution to the gas phase. However, we observe significant reductions in secondary structure contents (19.2 +/- 1.2% for myoglobin and 7.3 +/- 0.6% for beta-lactoglobulin) in specific regions predominantly composed of ionizable residues. Further mechanistic analysis suggests that alterations in protonation states of these residues after phase transition induce changes in their local interaction networks and backbone dihedral angles, which potentially promote the unfolding of secondary structures in the gas phase. We anticipate that similar protonation state induced unfolding may be observed in other proteins possessing distinct secondary structures. Further studies on a broader array of proteins will be essential to refine our understanding of protein structural behavior during the transition to the gas phase.
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| GB/T 7714 | Yang, Guiqian , Zhang, Lanbi , Xie, Song et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase [J]. | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) : 9374-9379 . |
| MLA | Yang, Guiqian et al. "Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase" . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS 15 . 37 (2024) : 9374-9379 . |
| APA | Yang, Guiqian , Zhang, Lanbi , Xie, Song , Wu, Juhong , Khan, Majid , Zhang, Yongqi et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) , 9374-9379 . |
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Sialylation, a critical post-translational modification, regulates glycoprotein structure and function by tuning their molecular heterogeneity. However, characterizing its subtle and dynamic conformational effects at the intact glycoprotein level remains challenging. We introduce a glycoform-resolved unfolding approach based on a high-throughput ion mobility-mass spectrometry (IM-MS) platform. This method integrates high-throughput unfolding with parallel fragmentation, enabling simultaneous analysis of sialylation patterns, stoichiometries, and their impact on conformational stability. Applying this approach to fetuin, we identified distinct sialylation patterns and their differential influence on protein conformation, namely sialylation-induced stabilization during early unfolding and increased flexibility in later unfolding stages. IM-MS-guided molecular dynamics simulations revealed that increased sialylation enhances the initial conformational stability, likely through enhanced electrostatic interactions and hydrogen bonding. These findings highlight the complex interplay between sialylation and protein dynamics and establish glycoform-resolved unfolding IM-MS as a powerful tool for characterizing glycoprotein conformational landscapes. A glycoform-resolved unfolding ion mobility-mass spectrometry approach reveals how sialylation patterns modulate glycoprotein conformational stability and dynamics, providing insights into the relationship between sialylation and protein structure.
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| GB/T 7714 | Jia, Yifei , Liu, Yichang , Wang, Yamei et al. Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry [J]. | CHEMICAL SCIENCE , 2024 , 15 (35) : 14431-14439 . |
| MLA | Jia, Yifei et al. "Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry" . | CHEMICAL SCIENCE 15 . 35 (2024) : 14431-14439 . |
| APA | Jia, Yifei , Liu, Yichang , Wang, Yamei , Li, Jinyu , Li, Gongyu . Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry . | CHEMICAL SCIENCE , 2024 , 15 (35) , 14431-14439 . |
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