Polymers
·
2022
·Vol. 14
·期 24
·5466
·
IF 4.967
Changcai Teng,Xiongyan Meng,Yeqin Hu,Hongzhao Mao,Huiting Li,Jing Yang,Tiantian Sun,Shuai Meng,Chengli Zong
Small synthetic TLR7/8-agonists can be used as vaccine adjuvants to enhance cell and humoral-mediated immune responses to specific antigens. Despite their potency, after local injection they can be dispersed to undesired body parts causing high reactogenicity, limiting their clinical applications. Here we describe a vaccination strategy that employs the covalent conjugate of a mannose and TLR7/8 agonist as a vaccine adjuvant to take advantage of mannose binding C-type lectins on dendritic cells to enhance the vaccine’s immunogenicity. The mannose-TLR7/8 agonist conjugate can self-assemble into nanoparticles with the hydrophilic mannose on the outside and hydrophobic TLR7/8 agonist inside. Although its ability to stimulate HEK-BlueTMhTLR7/8 cells dropped, it can efficiently stimulate mouse bone marrow-derived dendritic cells as indicated by the up-regulation of CD80 and CD86, and higher cytokine expression levels of TNF-α, IL6, and IL-12p70 than the native TLR7/8 agonist. In vivo, vaccination using the SARS-CoV-2 RBD trimer as the antigen and the conjugate as the adjuvant induced a significantly higher amount of IgG2a. These results suggest that the mannose-TLR7/8-agonist conjugate can be used as an effective vaccine adjuvant.Keywords:adjuvants;mannose;TLR7/8 agonist;immune responses;cytokines;antibody
研究领域:
免疫学
·
病毒学
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药学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Ying Xu,Jing Yang,Xiongyan Meng,Shuai Meng,Tiantian Sun,Ning Ding,Chengli Zong
Covalently linking an adjuvant to an antigenic protein enhances its immunogenicity by ensuring a synergistic delivery to the immune system, fostering a more robust and targeted immune response. Most adjuvant-protein conjugate vaccines incorporate only one adjuvant due to the difficulties in its synthesis. However, there is a growing interest in developing vaccines with multiple adjuvants designed to elicit a more robust and targeted immune response by engaging different aspects of the immune system for complex diseases where traditional vaccines fall short. Here, we pioneer the synthesis of a dual-adjuvants protein conjugate Vaccine 1 by assembling a toll-like receptor 7/8 (TLR7/8) agonist, an invariant natural killer T cell (iNKT) agonist with a clickable bicyclononyne (BCN). The BCN group can bio-orthogonally react with azide-modified severe acute respiratory syndrome coronavirus-2 receptor-binding domain (SARS-CoV-2 RBD) trimer antigen to give the three-component Vaccine 1 . Notably, with a mere 3 μg antigen, it elicited a balanced subclass of IgG titers and 20-fold more IgG2a than control vaccines, highlighting its potential for enhancing antibody-dependent cellular cytotoxicity. This strategy provides a practicable way to synthesize covalently linked dual immunostimulants. It expands the fully synthetic self-adjuvant protein vaccine that uses a single adjuvant to include two different types of adjuvants.
研究领域:
免疫学
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病毒学
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药物化学
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疫苗研发
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DOI
高影响因子
International Journal of Peptide Research and Therapeutics
·
2024
·Vol. 30
·期 5
·1-13
·
IF 2
Liu Ziyang,Wei Yuping,Zhang Man,Zhu Xingyan,Liu Kun
Angiotensin-converting enzyme-2 (ACE2) is a important cell surface receptor of SARS-CoV-2 S protein. The initial stage of SARS-COV-2 cell infection involves the binding of the S protein to ACE2. Hence, this work presents an innovative strategy to designing ACE2-based peptide inhibitors by considering the surface property and morphology of the S protein RBD. The aim is to develop a short peptide inhibitor that can effectively inhibit S protein-ACE2 interaction Through computational analysis and molecular simulation, the surface properties and morphology of S protein receptor-binding structural domain (RBD) were investigated, while the key residues of ACE2 ligand-binding structural domain (LBD) were identified based on their contributions and non-covalent interactions. Then, peptide inhibitors, consisting of ACE2 key residues, were developed by fitting to the surface characteristics and topographical features of the S protein RBD. Molecular simulation showed that two novel short peptides, IEPFF (I5) and WIEPFF (W6) had high affinity for S protein RBD but a low affinity for the cell membrane. Cellular adsorption studies demonstrated that both I5 and W6 effectively blocked ACE2-S protein binding without significant cytotoxicity. Flow cytometry analysis revealed that both I5 and W6 effectively inhibited S protein binding to the ACE2, resulting in a significant reduction (75 and 79%, respectively) in fluorescence intensity after 30 min of incubation at a concentration of 200 μM. Both I5 and W6 were excellent potential anti SARS-COV-2 drugs. This work provides an innovative perspective for the development of functional peptides for the prevention and management of SARS-COV-2.
研究领域:
生物化学
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分子生物学
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病毒学
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药学
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计算生物学
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产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Hongyu Zhu,Sen Yang,Jingyang Zhao,Liuyang Wang,Chenghao Gao,Yanan Sheng,Xuan Lin,Zhiguo Su,Kiichi Sato,Zhongyu Hu,Songping Zhang
All-trans retinoic acid (Ra) has been demonstrated to enhance the establishment of systemic and intestinal immunity for codelivered antigens; however, the extremely poor water solubility of Ra significantly limits its application in vaccines. Herein, leveraging the advantages of ionic liquids in modifying the physicochemical properties of small-molecule drugs, we synthesized a novel ionic liquid composed of choline and retinoic acid ([Cho][Ra]). Compared to Ra, [Cho][Ra] exhibited an 18165-fold increase in solubility at pH 7.4 and an acid-responsive Ra release behavior. The [Cho][Ra] was then formulated with the SARS-CoV-2 RBD antigen, and its adjuvant effects were comprehensively evaluated. The in vitro cellular studies indicated that at 50 μg Ra equivalent dose, the [Cho][Ra]@RBD showed significantly higher than RBD along in activation of BMDC and the expression of gut homing molecules, including C–C motif chemokine receptor 9 (CCR9, 10.55 folds), α4β7 integrin (13.29 folds), and lymph node migration molecule CCR7 (82.68 folds). Animal experiments showed that compared to RBD alone, [Cho][Ra]@RBD promoted the establishment of mucosal immunity in the intestines in mice at the early stage following subcutaneous immunization and elicited higher serum antibody levels. Furthermore, compared to RBD and Alum@RBD, [Cho][Ra]@RBD enhanced the formation of CD4+ TCM and CD8+ TCM cells, indicating stronger cellular immune responses. In summary, [Cho][Ra] showed potential adjuvant effects in enhancing the humoral and cellular immune responses, as well as in the establishment of intestinal mucosal immunity for RBD antigen without the need for delivery system, thereby offering promising prospects for applying Ra in vaccines.
研究领域:
免疫学
·
药剂学
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分子药理学
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疫苗学
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纳米医学
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药物递送
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转化医学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2021
·
IF 6.986
Guangyao Huang,Hongxin Zhao,Pan Li,Juanjuan Liu,Siyu Chen,Meihong Ge,Miao Qin,Guoliang Zhou,Yongtao Wang,Shaofei Li,Yizhuang Cheng,Qiang Huang,Junfeng Wang,Hongzhi Wang,Liangbao Yang
It is highly challenging to construct the best SERS hotspots for the detection of proteins by surface-enhanced Raman spectroscopy (SERS). Using its own characteristics to construct hotspots can achieve the effect of sensitivity and specificity. In this study, we built a fishing mode device to detect the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at low concentrations in different detection environments and obtained a sensitive SERS signal response. Based on the spatial resolution of proteins and their protein-specific recognition functions, SERS hotspots were constructed using aptamers and small molecules that can specifically bind to RBD and cooperate with Au nanoparticles (NPs) to detect RBD in the environment using SERS signals of beacon molecules. Therefore, two kinds of AuNPs modified with aptamers and small molecules were used in the fishing mode device, which can specifically recognize and bind RBD to form a stable hotspot to achieve high sensitivity and specificity for RBD detection. The fishing mode device can detect the presence of RBD at concentrations as low as 0.625 ng/mL and can produce a good SERS signal response within 15 min. Meanwhile, we can detect an RBD of 0.625 ng/mL in the mixed solution with various proteins, and the concentration of RBD in the complex environment of urine and blood can be as low as 1.25 ng/mL. This provides a research basis for SERS in practical applications for protein detection work.
研究领域:
分析化学
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纳米技术
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病毒学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
·
2026
·
IF 5.2
Qing Huang,Zefeng Hou,Yunong Zhao,Ruiqin Gu,Chengli Li,Minghong Yang,Huan Liu
Surface plasmon resonance (SPR) technology, boasting prominent advantages including anti-electromagnetic interference, high sensitivity, rapid response, label-free detection, and minimal sample consumption, holds broad application prospects in life sciences, clinical diagnostics, drug screening, and other related fields. However, current optical fiber biochemical sensors are generally plagued by poor probe practicality and stability, low refractive index sensitivity, and inadequate detection capability for ultra-low concentration biomolecules in clinical settings. In this study, we developed a low-cost, high-sensitivity optical fiber SPR biosensor for SARS-CoV-2 antigen detection in the standard sample, employing gold@silver‑platinum (Au@AgPt) core-shell nanospheres as the sensing enhancement module. Au@AgPt core-shell nanospheres possess unique localized surface plasmon resonance (LSPR) properties. When incident light interacts with the nanomaterial surface, it induces a localized electric field enhancement effect. This surface enhancement effect significantly amplifies the optical signal intensity, thereby effectively improving the sensor's detection sensitivity toward the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. This sensing platform achieves fg/mL-level detection sensitivity, excellent linearity, and rapid response performance, offering new technical support for expanding the application of optical fiber sensors in the quantitative detection of ultra-low concentration disease markers.
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DOI
高影响因子
Sensors & Diagnostics
·
2022
·Vol. 2
·期 2
·382-389
·
IF 0
Rui Han,Wenjie Hou,Yang Li,Min Chen,Caifeng Ding,Xiliang Luo
Antigen testing is an effective methodology for COVID-19 disease screening, and the receptor-binding domain of the SARS-CoV-2 spike glycoprotein (RBD) is recognized as a key biomarker for the diagnosis, treatment, and vaccination of COVID-19. However, the diagnosis of RBD directly in human biofluids remains a serious challenge owing to severe biological fouling in real samples. Herein, a sensitive electrochemical biosensor capable of detecting the RBD antigen in human blood was constructed based on a self-designed cyclic peptide. This cyclic peptide was designed to have good antifouling properties to resist nonspecific adsorption of proteins, etc. in blood, and the cyclic structure of the peptide was able to resist enzymatic hydrolysis by certain enzymes in blood, enhancing the stability of the peptide as well as the peptide-based biosensor. Compared with conventional linear peptides, the cyclic peptide possessed better antifouling properties and a much stronger anti-enzymatic hydrolysis ability. The electrochemical biosensor based on the cyclic peptide was capable of sensitively assaying RBD in the concentration range from 1.0 pg mL−1 to 100.0 ng mL−1, with a limit of detection of just 0.45 pg mL−1. Moreover, the biosensor was able to quantitatively detect RBD in real samples, and the results were more reliable than those measured with ELISA kits, especially in human blood with higher concentrations. This strategy of designing cyclic peptides for the construction of antifouling biosensors offered a new method for clinical detection of viral antigens in complex biological media like human blood.
研究领域:
生物化学
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分析化学
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生物医学工程
·
分子生物学
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DOI
Arabian Journal of Chemistry
·
2024
·
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
·
分子生物学
·
生物物理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD COMPOSITION AND ANALYSIS
·
2024
·
IF 4
Huanhuan Li,Qiyi Bei,Md. Mehedi Hassan,Murugavelu Marimuthu,Selorm Yao-Say Solomon Adade,Quansheng Chen,Muhammad Zareef
Abuse of tetracycline (TC) leads to the development of drug-resistant bacterial strains that threaten public health. This paper proposed a novel Cu 2+ -modulated UCNPs@RBD sensor for detecting TC. The sensor utilizes rhodamine B derivatives (RBD) that bind to Cu 2+ , forming RBD-Cu through a spirolactam open-loop reaction. The fluorescence of upconversion nanoparticles (UCNPs) is quenched by RBD-Cu via the inner filter effect (IFE). Upon addition of TC, TC-Cu forms due to electron-donor groups in TC, which decreases the generation of RBD-Cu, thereby enhancing the fluorescence of UCNPs . Under optimized conditions, the sensor exhibits remarkable accuracy across a concentration range of 50–50000 µg L −1 , with a limit of detection (LOD) of 1.72 µg L −1 . Moreover, the sensor demonstrates high selectivity for TC, validated by its application in food samples. The relative standard deviation (RSD) in real sample analysis was below 4.17 %, and the results were consistent with the HPLC method ( P > 0.05). Hence, the sensor exhibited a high level of sensitivity and reliability, making it suitable for the detection of TC in food.
研究领域:
食品科学
·
分析化学
·
生物传感
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产品关联
DOI
高影响因子
Signal Transduction and Targeted Therapy
·
2022
·Vol. 7
·期 1
·1-10
·
IF 38.104
Wu Jiajing,Nie Jianhui,Zhang Li,Song Hao,An Yimeng,Liang Ziteng,Yang Jing,Ding Ruxia,Liu Shuo,Li Qianqian,Li Tao,Cui Zhimin,Zhang Mengyi,He Peng,Wang Youchun,Qu Xiaowang,Hu Zhongyu,Wang Qihui,Huang Weijin
Emerging SARS-CoV-2 variants are the most serious problem for COVID-19 prophylaxis and treatment. To determine whether the SARS-CoV-2 vaccine strain should be updated following variant emergence like seasonal flu vaccine, the changed degree on antigenicity of SARS-CoV-2 variants and H3N2 flu vaccine strains was compared. The neutralization activities of Alpha, Beta and Gamma variants’ spike protein-immunized sera were analysed against the eight current epidemic variants and 20 possible variants combining the top 10 prevalent RBD mutations based on the Delta variant, which were constructed using pseudotyped viruses. Meanwhile, the neutralization activities of convalescent sera and current inactivated and recombinant protein vaccine-elicited sera were also examined against all possible Delta variants. Eight HA protein-expressing DNAs elicited-animal sera were also tested against eight pseudotyped viruses of H3N2 flu vaccine strains from 2011–2019. Our results indicate that the antigenicity changes of possible Delta variants were mostly within four folds, whereas the antigenicity changes among different H3N2 vaccine strains were approximately 10–100-fold. Structural analysis of the antigenic characterization of the SARS-CoV-2 and H3N2 mutations supports the neutralization results. This study indicates that the antigenicity changes of the current SARS-CoV-2 may not be sufficient to require replacement of the current vaccine strain.
研究领域:
病毒学
·
免疫学
·
流行病学
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DOI
PubMed
高影响因子
CHEMBIOCHEM
·
2024
·
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
·
细胞生物学
·
药理学
·
成像科学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）