Advanced Science
·
2025
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IF 14.1
Jianhong Qi,Yanxia Wang,Huan Chen,Kaitian Wu,Pei Zhou,Yue Dou,Bingqi Xiong,Wei Zhou
In recent years, pneumonia caused by multiple viruses has posed a significant threat to public health, particularly affecting vulnerable populations such as the elderly and immunocompromised individuals. Current treatments primarily focused on antiviral medications, lacking “miracle cure” and innovative approaches for the pathological damage caused by viruses. Since 2019, Traditional Chinese Medicine (TCM) has shown remarkable efficacy in treating coronavirus disease 2019 (COVID-19). However, the application is hindered by intricate mechanisms, variable quality, and slow onset. Clinically, Ge-Gen Decoction (GGD) effectively reduced the severity in patients with viral infections. Taking COVID-19 as a case, the bioactive ingredients from GGD: glabridin (GLA) and puerarin (PUE) are identified. Interestingly, it was discovered that PUE can self-assemble into a 3D hydrogel structure upon heating and cooling, namely PUE@gel. This process mirrored the formation of gel-like precipitates in GGD post-decoction. Motivated by this phenomenon, a decoction-mimicking drug delivery system, glabridin─puerarin self-assembled hydrogel (GLA-PUE@gel) was constructed, which exhibits strong anti-inflammatory and antioxidant properties, comparable to GGD at the same dosage. Additionally, PUE that has a high biosafety threshold can competitively bind to angiotensin converting enzyme 2 (ACE2) on host cells, preventing SARS-CoV-2 from invading. This study offered a promising approach for treating virus-induced lung injury.
研究领域:
药理学
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中药学
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生物材料
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病毒学
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产品关联
DOI
PubMed
高影响因子
Computational and Structural Biotechnology Journal
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2023
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IF 6
Boyu Pan,Senbiao Fang,Liangjiao Wang,Zhanyu Pan,Min Li,Liren Liu
The emergence of SARS-CoV-2-Spike mutants not only enhances viral infectivity but also lead to treatment failure. Gaining a comprehensive understanding of the molecular binding mode between the mutant SARS-CoV-2-Spike and human ACE2 receptor is crucial for therapeutic development against this virus. Building upon our previous predictions and verifications regarding heightened viral infectivity of six potential SARS-CoV-2-Spike mutants, this study aims to further investigate the potential disruption of the interaction between these mutants and ACE2 by quercetin, a Chinese herbal compound. Molecular docking and dynamics simulations results reveal that the binding sites of quercetin particularly enriched around a specific “cavity” at the interface of Spike/ACE2 complex, indicating a favorable region for quercetin to interfere with Spike/ACE2 interaction. Virus infection assay confirms that quercetin not only attenuates wild-type virus infectivity but also suppresses the infectivity of all six tested SARS-CoV-2-Spike mutants. Therefore, quercetin represents a promising therapeutic candidate against both wild-type and potential future variants of SARS-CoV-2 exhibiting high viral infectivity.
研究领域:
病毒学
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药理学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2026
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IF 6.2
Xiaoyu Ma,Zhuang Zhang,Dandan Yang,Hui Wang,Hao Zhang,Yue Yang,Siying Li,Yuping Shan
Beyond the canonical angiotensin-converting enzyme 2 (ACE2)-mediated entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells, basigin (BSG) and dipeptidyl peptidase 4 (DPP4) may also act as alternative receptors that can facilitate viral attachment and subsequent endocytosis. Herein, we analyzed the binding efficiency and binding dynamics of SARS-CoV-2 virus-like particles (VLPs), mediated by BSG and DPP4 at the single-particle level, by combining super-resolution direct stochastic optical reconstruction microscopy (dSTORM) and single-molecule force spectroscopy (SMFS). dSTORM imaging demonstrated that DPP4 exhibits higher surface expression levels than BSG on HepG2 cells. However, SARS-CoV-2 VLPs display a distinct preference for BSG-dependent cellular entry. Using SMFS, we further probed the binding dynamics between the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD) and these two receptors. The results demonstrated that RBD-BSG exhibits greater stability and a more rapid formation rate compared to RBD-DPP4. Subsequently, a real-time force tracing technique was used to show that BSG-mediated VLP entry requires lower force and faster speed compared with DPP4-mediated entry. In particular, we confirmed that the structural integrity of intramolecular disulfide bonds within the RBD is indispensable for mediating high-affinity receptor binding. These findings elucidate the distinct receptor-mediated endocytic dynamic mechanisms underlying SARS-CoV-2 entry mediated by BSG and DPP4, expanding our understanding of viral invasion beyond the ACE2 pathway and providing insights into potential intervention strategies targeting viral infection.
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DOI
PubMed
高影响因子
Molecular Biomedicine
·
2026
·Vol. 7
·期 1
·122
·
IF 13
Wang Yifei,Xu Jinghan,Chen Yiquan,Xiao Xin,Zhu Yiru,Yu Liyang,Shi Wen,Li Jingchao,Li Jianhua,Zhu Chenggang
The COVID-19 pandemic and its protracted consequences underscore the urgent need for more effective antiviral strategies. Current antiviral strategies face a persistent challenge achieving sufficient viral suppression while minimizing off-target toxicity, particularly against such highly mutable viruses. Here, we describe a Receptor-Drug Conjugate (RDC) strategy, in which a therapeutic payload is covalently linked to a decoy receptor, enabling virus-triggered targeted intracellular delivery. Angiotensin-converting enzyme 2 (ACE2), as the essential receptor for SARS-CoV-2 entry, has been widely exploited for virus-neutralizing strategies. Targeting SARS-CoV-2 as a proof-of-concept, we conjugated peptide nucleic acids (PNAs) designed to target the viral ORF1ab region (±30 bp) to ACE2-Fc. The ACE2-PNA conjugate demonstrated superior inhibitory efficacy against multiple SARS-CoV-2 variants relative to ACE2-Fc alone. We confirmed that ACE2-PNA retains the extracellular neutralization activity of soluble ACE2, while being selectively internalized into virus-infected cells via virus-mediated endocytosis. Owing to its inherent protease resistance, the PNA component remains intact upon cytoplasmic entry and subsequently exerts antisense inhibitory activity against viral RNA. The mechanistic feasibility of ACE2-PNA was further validated in a mouse model. Collectively, RDC represents a novel virus-triggered targeted delivery platform that confers dual antiviral efficacy through extracellular virion neutralization and intracellular inhibition of viral replication. It has significant implications for reducing off-target toxicity and enhancing antiviral potency, and is furthermore readily adaptable to diverse viral pathogens and therapeutic payloads.
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DOI
高影响因子
Journal of Inflammation Research
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2022
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IF 4.631
Huixia Feng,Guilin Chen,Yongli Zhang,Mingquan Guo
Background Dysosma versipellis ( D. versipellis ) has been traditionally used as a folk medicine for ages. However, the specific phytochemicals responsible for their correlated anti-inflammatory, anti-proliferative and antiviral activities remain unknown. Purpose This study aimed to explore the specific active components in D. versipellis responsible for its potential anti-inflammatory, anti-proliferative, and antiviral effects, and further elucidate the corresponding mechanisms of action. Methods Bioaffinity ultrafiltration coupled to liquid chromatography–mass spectrometry (UF-LC/MS) was firstly hired to fast screen for the anti-inflammatory, anti-proliferative and antiviral compounds from rhizomes of D. versipellis , and then further validation was conducted using in vitro inhibition assays and molecular docking. Results A total of 12, 12, 9 and 12 phytochemicals with considerable affinities to Topo I, Topo II, COX-2 and ACE2 were fished out, respectively. The anti-proliferative assay in vitro indicated that podophyllotoxin and quercetin exhibited comparably strong inhibitory rates on A549 and HT-29 cells compared with 5-FU and etoposide. Meanwhile, kaempferol displayed prominent dose-dependent inhibition against COX-2 with IC 50 value at 0.36 ± 0.02 μM lower than indomethacin at 0.73 ± 0.07 μM. Furthermore, quercetin exerted stronger inhibitory effect against ACE2 with IC 50 value at 104.79 ± 8.26 μM comparable to quercetin 3- O -glucoside at 135.25 ± 6.54 μM. Conclusion We firstly showcased an experimental investigation on the correlations between bioactive phytochemicals of D. versipellis and their multiple drug targets reflecting its potential pharmacological activities, and further constructed a multi-target and multi-component network to decipher its empirical traditional applications. It could not only offer a reliable and valuable experimental basis to better comprehend the curative effects of D. versipellis but also provide more new insights and strategies for other traditional medicinal plants.
研究领域:
药理学
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生物化学
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传统医学
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植物科学
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产品关联
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
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IF 5.3
Chuanxi Tian,Jinyue Zhao,Qian Wang,Keke Luo,Shuang Zhao,Li Wan,Jiarui Li,Kaile Ma,Yanyan Zhou,Min Li
Background Huashi Baidu granule (HSBD), an approved herbal formula for treating COVID-19, demonstrates safety and efficacy. Despite its market approval, the detailed methodology and identification of its active components remain unexplored, leaving its bioactive constituents and action mechanisms unclear. Methods This study investigated the potential mechanisms of HSBD’s active ingredient in treating COVID-19. Our approach integrated various techniques, including the UHPLC-QqQ-MS/MS method, analysis of the GEO database, network pharmacology, surface plasmon resonance, molecular docking and molecular dynamics simulations, to formulate a comprehensive research strategy. Results The UHPLC-QqQ-MS/MS method employed for HSBD analysis proved stable, reliable, and reproducible. We identified 25 principal components in HSBD, with 7 compounds detected in plasma, namely Pogostone, P-Hydroxybenzoic acid, Paeoniflorin, Rhein, Emodin, Ephedrine hydrochloride, and Pseudoephedrine hydrochloride. Protein-Protein Interaction (PPI) network analysis identified MMP9 as a pivotal target. Surface plasmon resonance analysis revealed that Paeoniflorin and Rhein exert their antiviral effects by interacting with RBD and ACE2. In contrast, Emodin’s antiviral mechanism predominantly involves binding to MMP9. Molecular docking results indicated strong binding affinities of Rhein and Paeoniflorin to the hACE2 protein, and high binding affinities of Emodin to the MMP9 protein, all of which were corroborated by molecular dynamics simulations. Conclusion We investigated the methodology and identified the active components of HSBD, focusing on those absorbed into the plasma, to elucidate the effective material basis of HSBD in the treatment of COVID-19, our research offered insightful exploration into its mechanisms of action against COVID-19.
研究领域:
药理学
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医学
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生物化学
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分子生物学
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产品关联
DOI
高影响因子
CELL RESEARCH
·
2021
·Vol. 31
·期 10
·1047-1060
·
IF 25.617
Hu Wei,Zhang Yong,Fei Panyu,Zhang Tongtong,Yao Danmei,Gao Yufei,Liu Jia,Chen Hui,Lu Qiao,Mudianto Tenny,Zhang Xinrui,Xiao Chuxuan,Ye Yang,Sun Qiming,Zhang Jing,Xie Qi,Wang Pei-Hui,Wang Jun,Li Zhenhai,Lou Jizhong,Chen Wei
The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike’s S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike’s receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~10 3 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 10 6 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.
研究领域:
病毒学
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分子生物学
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生物物理学
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DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2024
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IF 4.9
Yansheng Liu,Haonan Hu,Xiaobo Jia,Jin Zhou,Hongli Li,Xiaohong Wang,Shaohui Zhang,Haixin Chang,Fuchong Li,Guofu Wang
This study reported a sandwich SERS structure in detecting SARS-CoV-2 spike protein (SARS-CoV-2 S protein) with high performance. The periodic Ag nanoarrays (AgNAs) functionalized with angiotensin-converting enzyme 2 (ACE2) were utilized as the bottom structure to specifically bound to the SARS-CoV-2 S protein. A complex of SARS-CoV-2 S protein antibody and 4-mercaptobenzoic acid (4-Mba) modified Au nanoparticles (AuNPs@4-Mba@Antibody) were used as nanotags and top SERS enhancing structures. By utilized the “hot spots” in parallel and perpendicular directions, the SERS signals of the 4-Mba as reporters were largely enhanced. By modulated the diameters and the heights of the AgNAs, the SERS performance of the sandwich structures was optimized by using R6G as a stand analyst with limits of detection (LOD) of 1 × 10 −9 M. By applied the optimized sandwich structures in detecting SARS-CoV-2 S protein in phosphate buffered saline (PBS) and pharyngeal swabs solution (PSS), the proposed sandwich structure illustrates a high performance, and the LODs were 0.1 fg mL −1 and 1 fg mL −1 , respectively. This study presented an efficient way to construct a sandwich SERS structure in directly detecting SARS-CoV-2 S protein and this method illustrates a good potential in viral detection.
研究领域:
生物医学工程
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病毒学
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分析化学
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产品关联
DOI
高影响因子
CHEMBIOCHEM
·
2024
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IF 2.6
Chunyu Yan,Wei Zhou,Yan Zhang,Xuelian Zhou,Qinglong Qiao,Lu Miao,Zhaochao Xu
In this study, super-resolution structured illumination microscope (SIM) was used to analyze molecular mechanism of endocytic acidification inhibitors in the SARS-CoV-2 pandemic, such as Chloroquine (CQ), Hydroxychloroquine (HCQ) and Bafilomycin A1 (BafA1). We fluorescently labeled the SARS-CoV-2 RBD and its receptor ACE2 protein with small molecule dyes. Utilizing SIM imaging, the real-time impact of inhibitors (BafA1, CQ, HCQ, Dynasore) on the RBD-ACE2 endocytotic process was dynamically tracked in living cells. Initially, the protein activity of RBD and ACE2 was ensured after being labeled. And then our findings revealed that these inhibitors could inhibit the internalization and degradation of RBD-ACE2 to varying degrees. Among them, 100 nM BafA1 exhibited the most satisfactory endocytotic inhibition (~63.9%) and protein degradation inhibition (~97.7%). And it could inhibit the fusion between endocytic vesicles in the living cells. Additionally, Dynasore, a widely recognized dynein inhibitor, also demonstrated cell acidification inhibition effects. Together, these inhibitors collectively hinder SARS-CoV-2 infection by inhibiting both the viral internalization and RNA release. The comprehensive evaluation of pharmacological mechanisms through super-resolution fluorescence imaging has laid a crucial theoretical foundation for the development of potential drugs to treat COVID-19.
研究领域:
病毒学
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细胞生物学
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药理学
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成像科学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 7
·1749-1757
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IF 6.15
Li Dan,Ding Jin,Liu Te-li,Wang Feng,Meng Xiang-xi,Liu Song,Yang Zhi,Zhu Hua
The spike protein of SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) of human respiratory epithelial cells, which leads to infection. Furthermore, low-dose radiation has been found to reduce inflammation and aid the curing of COVID-19. The receptor binding domain (RBD), a recombinant spike protein with a His tag at the C-terminus, binds to ACE2 in human body. We thus constructed a radioiodinated RBD as a molecule-targeted probe to non-invasively explore ACE2 expression in vivo, and to investigate radiotherapy pathway for inhibiting ACE2. RBD was labeled with [ 124 I]NaI using an N-bromosuccinimide (NBS)-mediated method, and 124 I-RBD was obtained after purification with a specific activity of 28.9 GBq/nmol. Its radiochemical purity was (RCP) over 90% in saline for 5 days. The dissociation constant of 124 I-RBD binding to hACE2 was 75.7 nM. The uptake of 124 I-RBD by HeLa ACE+ cells at 2 h was 2.96% ± 0.35%, which could be substantially blocked by an excessive amount of RBD, and drop to 1.71% ± 0.23%. In BALB/c mice, the biodistribution of 124 I-RBD after intravenous injection showed a moderate metabolism rate, and its 24 h-post injection (p.i.) organ distribution was similar to the expression profile in body. Micro-PET imaging of mice after intrapulmonary injection showed high uptake of lung at 1, 4, 24 h p.i.. In conclusion, the experimental results demonstrate the potential of 124 I-RBD as a novel targeted molecular probe for COVID-19. This probe may be used for non-invasive ACE2 mapping in mammals.
研究领域:
放射学
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分子生物学
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病毒学
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核医学
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传染病学
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产品关联
DOI
PubMed
高影响因子
EXPERT SYSTEMS WITH APPLICATIONS
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2023
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IF 8.5
Guanxing Chen,Haohuai He,Lu Zhao,Qiujie Lv,Calvin Yu-Chian Chen
The COVID-19 pandemic’s profound impact on global health and the economy underscores the need for new computational strategies to rapidly identify potential antiviral drugs against emerging and re-emerging infectious diseases. AI-based drug repurposing methods have the potential to significantly shorten the drug discovery process, rendering them a crucial and efficacious approach for screening anti-SARS-CoV-2 compounds. In this paper, we proposed GINCM-DTA, an AI-based graph isomorphism network with protein contact map representation for drug–target affinity (DTA) prediction, and presented the COVID-DTA dataset for SARS-CoV-2-specific drug repurposing. Pre-training GINCM-DTA on large-scale Davis and KIBA datasets achieved state-of-the-art performance, while fine-tuning on the COVID-DTA dataset using transfer learning resulted in a mean square error of 0.026 and concordance index of 0.967. Utilizing the fine-tuned GINCM-DTA model, we predicted DTAs for drugs against SARS-CoV-2 main targets, focusing on key conserved proteins and unmutated spike proteins for virtual screening. We integrated GINCM-DTA predictions with molecular docking simulations to identify five candidates. In vitro assays revealed Hydralazine (5.737 nM) as a potential inhibitor of ACE2 and TMPRSS2, effectively blocking SARS-CoV-2 infection. Moreover, the results highlight the potential of Hydralazine as a broad-spectrum drug candidate, demonstrating its efficacy in obstructing the binding between ACE2 and spike proteins of multiple Omicron variants, including the currently dominant strains BQ.1, BQ.1.1, XBB.1.5, and XBB.1.16. Our method offers a novel computational strategy for COVID-19 antiviral screening and prepares for potential future epidemics incited by emerging viruses.
研究领域:
人工智能
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药物发现
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计算生物学
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病毒学
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药学
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产品关联
DOI
高影响因子
ANALYTICAL CHEMISTRY
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2022
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IF 8.008
Chaowei Han,Tianbao Dong,Pengcheng Wang,Feimeng Zhou
Unlike conventional surface plasmon resonance (SPR) using an antifouling film to anchor biomolecules and a reference channel for background subtraction, SPR microscopy for single-cell analysis uses a protein- or polypeptide-modified gold substrate to immobilize cells and a cell-free area as the reference. In this work, we show that such a substrate is prone to nonspecific adsorption (NSA) of species from the cell culture media, resulting in false background signals that cannot be correctly subtracted. To obtain accurate kinetic results, we patterned a dual-channel substrate using a microfluidic device, with one channel having poly-l-lysine deposited in situ onto a preformed polyethylene glycol (PEG) self-assembled monolayer for cell immobilization and the other channel remaining as PEG-covered for reference. The two 2.0 mm-wide channels are separated by a 75 μm barrier, and parts of the channels can be readily positioned into the field of view of an SPR microscope. The use of this dual-channel substrate for background subtraction is contrasted with the conventional approach through the following binding studies: (1) wheat germ agglutinin (WGA) attachment to the N-acetyl glucosamine and N-acetyl-neuraminic acid sites of glycans on HFF cells, and (2) the S1 protein of the COVID-19 virus conjugation with angiotensin-converting enzyme 2 (ACE2) on the HEK293 cells. Both studies revealed that interferences by NSA and the surface plasmon polariton wave diffracted by cells can be excluded with the dual-channel substrate, and the much smaller refractive index changes caused by the injected solutions can be correctly subtracted. Consequently, sensorgrams with higher signal-to-noise ratios and shapes predicted by the correct binding model can be obtained with accurate kinetic and affinity parameters that are more biologically relevant. The affinity between S1 protein and ACE2 is comparable to that measured with recombinant ACE2, yet the binding kinetics is different, suggesting that the cell membrane does impose a kinetic barrier to their interaction.
研究领域:
生物物理学
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生物化学
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微流控技术
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细胞生物学
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分析化学
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DOI
PubMed
高影响因子
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