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Enhancing tumor-associated carbohydrate antigen vaccine efficacy through synergistic antibody recruitment:A combined strategy targeting TACA heterogeneity 认领 引用
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作者 Dan Li Haofei Hong +3 位作者 Han Lin Teng Xu Zhifang Zhou Zhimeng Wu 《Chinese Chemical Letters》 SCIE CAS CSCD 2026年第5期416-420,共5页
Tumor-associated carbohydrate antigen(TACA)-based cancer vaccines face clinical challenges due to heterogeneous TACA expression,which compromises antibody-mediated tumor recognition and leads to suboptimal therapeutic... Tumor-associated carbohydrate antigen(TACA)-based cancer vaccines face clinical challenges due to heterogeneous TACA expression,which compromises antibody-mediated tumor recognition and leads to suboptimal therapeutic outcomes.To address this limitation,we report a combined strategy that integrates vaccination with TACA-based antibody-recruiting molecules.This approach simultaneously redirects antiTACA antibodies to tumor cells expressing a secondary target,thereby enhancing the efficacy of TACA-based vaccines.Using sialyl-Tn(sTn)as a model TACA and epidermal growth factor receptor(EGFR)and human epidermal growth factor receptor 2(HER2)as model protein targets,we designed two nanobody(Nb)-sTn conjugates as TACA-based antibody-recruiting molecules:EGFR-targeting 7D12-sTn and HER2-targeting C7b-s Tn.These conjugates were synthesized via sortase A-mediated ligation and demonstrated strong binding profiles.Importantly,they effectively redirected anti-s Tn antibodies,generated by the Theratope vaccine,to target cells in situ,significantly improving the recognition of tumor cells by antis Tn antibodies.The synergistic potential of these conjugates in amplifying the therapeutic effect of the s Tn-KLH vaccine was further validated through complement-dependent cytotoxicity assays.This innovative strategy represents a highly promising approach to overcome the clinical challenges posed by TACA heterogeneity in cancer vaccine development. 展开更多
关键词 Cancer vaccine Carbohydrates Immunotherapies Nanobody Sialyl-Tn
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Causal Associations between Particulate Matter 2.5(PM2.5),PM2.5 Absorbance,and Inflammatory Bowel Disease Risk:Evidence from a Two-Sample Mendelian Randomization Study 认领 引用
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作者 Xu Zhang Zhimeng Wu +7 位作者 Lu Zhang Binglong Xin Xiangrui Wang Xinlan Lu Guifang Lu Mudan Ren Shuixiang He Yarui Li 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2025年第2期167-177,共11页
Objective Several epidemiological observational studies have related particulate matter(PM)exposure to Inflammatory bowel disease(IBD),but many confounding factors make it difficult to draw causal links from observati... Objective Several epidemiological observational studies have related particulate matter(PM)exposure to Inflammatory bowel disease(IBD),but many confounding factors make it difficult to draw causal links from observational studies.The objective of this study was to explore the causal association between PM2.5exposure,its absorbance,and IBD.Methods We assessed the association of PM2.5and PM2.5absorbance with the two primary forms of IBD(Crohn’s disease[CD]and ulcerative colitis[UC])using Mendelian randomization(MR)to explore the causal relationship.We conducted two-sample MR analyses with aggregated data from the UK Biobank genome-wide association study.Single-nucleotide polymorphisms linked with PM2.5concentrations or their absorbance were used as instrumental variables(IVs).We used inverse variance weighting(IVW)as the primary analytical approach and four other standard methods as supplementary analyses for quality control.Results The results of MR demonstrated that PM2.5had an adverse influence on UC risk(odds ratio[OR]=1.010;95%confidence interval[CI]=1.001–1.019,P=0.020).Meanwhile,the results of IVW showed that PM2.5absorbance was also causally associated with UC(OR=1.012;95%CI=1.004–1.019,P=0.002).We observed no causal relationship between PM2.5,PM2.5absorbance,and CD.The results of sensitivity analysis indicated the absence of heterogeneity or pleiotropy,ensuring the reliability of MR results.Conclusion Based on two-sample MR analyses,there are potential positive causal relationships between PM2.5,PM2.5absorbance,and UC. 展开更多
关键词 Particulate matter 2.5 Inflammatory bowel disease Mendelian randomization
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Recent progress of fully synthetic carbohydrate-based vaccine using TLR agonist as build-in adjuvant 认领 引用 被引量：6
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作者 Zhifang Zhou Hart Lin +1 位作者 Chen Li Zhimeng Wu 《Chinese Chemical Letters》 SCIE CAS CSCD 2018年第1期19-26,共8页
Fully synthetic vaccine,in which one or multi-molecular antigens are conjugated to a synthetic carrier with well-defined chemical structure,is a new direction to develop carbohydrate-based vaccine against cancer and p... Fully synthetic vaccine,in which one or multi-molecular antigens are conjugated to a synthetic carrier with well-defined chemical structure,is a new direction to develop carbohydrate-based vaccine against cancer and pathogens.Toll like receptor(TLR)agonists with the ability to stimulate immune response have been widely investigated and been applied as build-in adjuvants to construct fully synthetic vaccines.In particular,remarkable progress has been achieved in recent years in the development of vaccines constructed with the agonists of TLRI 2,TLR2/6 and TLR4 and tumor-associated carbohydrate antigens(TACAs).These di-,tri-or multi-component vaccine candidates showed attractive immunologi-cal properties.This review highlights recent advances in developing full synthetic carbohydrate antigen based vaccines,with an emphasis on the structure-activity relationships that provide a primary basis for future vaccine design and immunotherapy developing. 展开更多
关键词 Fully synthetic vaccine TLR agonist Build-in adjuvant Carbohydrate-based vaccine TACAs
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Efficient expression of sortase A from Staphylococcus aureus in Escherichia coli and its enzymatic characterizations 认领 引用 被引量：3
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作者 Zhimeng Wu Haofei Hong +1 位作者 Xinrui Zhao Xun Wang 《Bioresources and Bioprocessing》 EI 2017年第1期493-502,共10页
Background:Sortase A(SrtA)is a transpeptidase found in Staphylococcus aureus,which is widely used in site-specific protein modification.However,SrtA was expressed in Escherichia coli(E.coli)in rather low level(ranging... Background:Sortase A(SrtA)is a transpeptidase found in Staphylococcus aureus,which is widely used in site-specific protein modification.However,SrtA was expressed in Escherichia coli(E.coli)in rather low level(ranging from several milligrams to 76.9 mg/L at most).The present study aims to optimize fermentation conditions for improving SrtA expression in E.coli.Results:Under the optimized media(0.48 g/L glycerol,1.37 g/L tryptone,0.51 g/L yeast extract,MOPS 0.5 g/L,PBS buffer 180 mL/L)and condition(30℃ for 8 h)in a 7-L fermentor,the enzyme activity and the yield of SrtA reached 2458.4±115.9 U/mg DCW and 232.4±21.1 mg/L,respectively,which were higher by 5.8-and 4.5-folds compared with initial conditions,respectively.The yield of SrtA also represented threefold increase than the previously reported maximal level.In addition,the enzymatic characterizations of SrtA(optimal temperature,optimal pH,the influence of metal irons,and tolerance to water-soluble organic solvents)were determined.Conclusions:Enhanced expression of SrtA was achieved by optimization of medium and condition.This result will have potential application for production levels of SrtA on an industry scale.Moreover,the detailed enzymatic characterizations of SrtA were examined,which will provide a useful guide for its future application. 展开更多
关键词 Sortase A Escherichia coli Response surface methodology 7-L fermentor Enzymatic characterizations
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Supramolecular complex glycoconjugate vaccine generates self-enhancement effects for carbohydrate antigen delivery 认领 引用 被引量：3
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作者 Han Lin Yanchun Li +6 位作者 Kun Zhou Dan Li Hangyan Yu Jie Zhao Haofei Hong Zhifang Zhou Zhimeng Wu 《Chinese Chemical Letters》 SCIE CAS CSCD 2024年第2期317-322,共6页
Targeting delivery of tumor-associated carbohydrate antigen(TACA)-based vaccine to antigen-presenting cells(APCs)mediated by endogenous antibodies can improve the immunogenicity of TACA.However,an essential requiremen... Targeting delivery of tumor-associated carbohydrate antigen(TACA)-based vaccine to antigen-presenting cells(APCs)mediated by endogenous antibodies can improve the immunogenicity of TACA.However,an essential requirement of this approach is to generate high titers of endogenous antibodies in vivo through pre-immunization,which complicates the immunization procedure and may cause side effects.Herein,we report a new generation of APC-targeting TACA-based supramolecular complex vaccine,assembled by sialyl Thomsen-nouveau-bovine serum albumin-adamantine(sTn-BSA-Ada)and heptavalent rhamnose(Rha)-modifiedβ-cyclodextrin(β-CD)via host-guest interaction.The complex vaccine retained anti-Rha antibodies recruiting capability and facilitated the APCs uptake of the vaccine via the interaction of the Fc-domain with the Fc receptors on APCs.We demonstrate that direct immunization of complex vaccine elicited anti-Rha and anti-sTn specific immune response synchronously,generating a novel self-enhancement effect that can improve the antigen delivery to APCs in high efficacy.The structure-activity relationship(SAR)study proved that complex vaccine 4 with polyethylene glycol 6(PEG 6)linker in host molecule provoked a robust and specific sTn immune response comparable to the pre-immunization approach.The antisera induced by complex vaccine,either through direct immunization or pre-immunization,exhibited equal potency of cytotoxicity against the sTn expression cancer cells.This study provides a general platform for TACA-based vaccines with self-enhancement effects without the need for pre-immunization. 展开更多
关键词 Glycoconjugate vaccine Endogenous antibody APC-targeting Supramolecular complex sTn antigen
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Synthesis of DNP-modified GM3-based anticancer vaccine and evaluation of its immunological activities for cancer immunotherapy 认领 引用 被引量：1
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作者 Han Lin Haofei Hong +3 位作者 Lipeng Feng Jie Shi Zhifang Zhou Zhimeng Wu 《Chinese Chemical Letters》 SCIE CAS CSCD 2021年第12期4041-4044,共4页
Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2... Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2,4-ditrophenyl(DNP)-modified GM3 intermediate was synthesized chemoenzymatically and conjugated to keyhole limpet hemocyanin(KLH), and the resulting bioconjugate was tested for its potential as a vaccine candidate. Mice immunological studies revealed that the DNP-modified GM3(GM3-NHDNP) analog elicited strong and rapid immune responses by recruiting anti-DNP antibodies to facilitate the targeted delivery of the vaccine construct to antigen processing cells(APCs). Moreover, the endogenously produced anti-DNP antibodies, together with the elicited antibodies against GM3-NHDNP, may synergistically promote tumor binding and cancer cell death when the cancer cell surfaces are glycoengineered to express the GM3-NHDNP antigen. 展开更多
关键词 GM3 Cancer vaccine Anti-DNP antibodies Glycoengineering Tumor-associated carbohydrate antigen
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MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction elicit robust immune responses 认领 引用
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作者 Hangyan Yu Han Lin +9 位作者 Yuntian Xie Mengyuan Qu Min Jiang Jie Shi Haofei Hong Hongrui Xu Ling Li Guochao Liao Zhimeng Wu Zhifang Zhou 《Chinese Chemical Letters》 SCIE CAS CSCD 2022年第11期4882-4885,共4页
We construct MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction.These vaccines based on non-covalent assembling can provoke robust immune responses,including high level o... We construct MUC1 vaccines usingβ-cyclodextrin grafted chitosan(CS-g-CD)as carrier via host-guest interaction.These vaccines based on non-covalent assembling can provoke robust immune responses,including high level of specific antibodies and cytokines.The induced antibodies can specifically recognize tumor cells and mediate cytotoxicity against tumor cells.These results indicate that CS-g-CD with strong immunostimulatory activities can be a straightforward platform for peptide-based vaccine construction. 展开更多
关键词 β-Cyclodextrin grafted chitosan MUC1 antigen Cancer vaccine Host-guest interaction Vaccine carrier Tn antigen
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Synthesis and immunological study of a glycosylated wall teichoic acid-based vaccine against Staphylococcus aureus 认领 引用
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作者 Peng Shen Han Lin +2 位作者 Yikai Bao Haofei Hong Zhimeng Wu 《Chinese Chemical Letters》 SCIE CAS CSCD 2023年第4期193-197,共5页
Staphylococcus aureus wall teichoic acids(WTAs) are attractive targets for antibacterial vaccine development. In this study, three core glycosylated WTA structure, including α-1,4-Glc NAc, β-1,4-Glc NAc andβ-1,3-Gl... Staphylococcus aureus wall teichoic acids(WTAs) are attractive targets for antibacterial vaccine development. In this study, three core glycosylated WTA structure, including α-1,4-Glc NAc, β-1,4-Glc NAc andβ-1,3-Glc NAc modified ribitol phosphates containing a linker are chemically synthesized and conjugated with tetanus toxin(TT) carrier protein as vaccine candidates. In vivo immunological studies demonstrate that the synthesized glycosylated WTAs display high immunogenicity and all conjugates provoke strong immune responses and elicit high levels of specific IgG antibodies against the Glc NAc-modified WTA. Furthermore, antibodies elicited by the vaccine candidates remain the capability to recognize S. aureus cells and display significant opsonophagocytic activity to clear S. aureus. This study demonstrates that the core structure of glycosylated WTAs are effective antigens for constructing anti-S. aureus vaccines to prevent and control S. aureus infections. 展开更多
关键词 WTAs Staphylococcus aureus GlcNAc modifications Glycoconjugates Antibacterial vaccine
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Tumor Cell-Specific Metabolic Labelling of Surface Sialoglycans and Post-Click with Multivalent Rhamnose Enable Precise Immune Killing by Endogenous Antibody 认领 引用
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作者 Haofei Hong Yanchun Li +4 位作者 Dan Li Han Lin Jie Zhao Zheng Wang Zhimeng Wu 《Chinese Journal of Chemistry》 SCIE CAS CSCD 2025年第1期46-52,共7页
We report the design and development of aβ-glucuronidase(β-Glu)-responsive ManNAz derivative,Glu-AAM,for tumor-selective metabolic glycoengineering.Glu-AAM enables specific labeling of tumor cell surface sialoglycan... We report the design and development of aβ-glucuronidase(β-Glu)-responsive ManNAz derivative,Glu-AAM,for tumor-selective metabolic glycoengineering.Glu-AAM enables specific labeling of tumor cell surface sialoglycans in the presence of overexpressedβ-Glu in cancer cells,including breast,leukemia,and colorectal cancer cells.We demonstrate the high selectivity and efficiency of Glu-AAM-mediated metabolic glycoengineering across multiple cancer cell lines.Furthermore,we synthesized multivalent antibody-recruiting molecules(DBCO-Rha)that can be covalently attached to the azido-modified tumor cell surface,leading to potent antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity.The octameric DBCO-Rha8 construct exhibited the most effective immune response.This integrated strategy ofβ-Glu-responsive metabolic glycoengineering and antibody-recruiting immunotherapy provides a promising platform for targeted cancer therapies and expands the toolbox of metabolic glycoengineering for cancer immunotherapy. 展开更多
关键词 Metabolic glycoengineering β-Glucuronidase Antibody recruitment Multivalent rhamnose Cancer immunotherapy Bioimaging Clickchemistry Carbohydrates
Enhanced high-temperature performance of T7 RNA polymerase by greedy accumulation-directed evolution of thermostability 认领 引用 被引量：1
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作者 Qian Liu Cheng Lu +5 位作者 Ronglian Xu Ling Zhang Zhifang Zhou Haofei Hong Zhimeng Wu Jie Shi 《Systems Microbiology and Biomanufacturing》 EI CAS CSCD 2025年第3期1154-1167,共14页
T7 RNA polymerase(T7 RNAP)-catalyzed in vitro transcription(IVT)is the gold standard manufacturing process for large-scale production of therapeutic mRNA molecules.However,the undesired catalytic activity of T7 RNAP c... T7 RNA polymerase(T7 RNAP)-catalyzed in vitro transcription(IVT)is the gold standard manufacturing process for large-scale production of therapeutic mRNA molecules.However,the undesired catalytic activity of T7 RNAP concomitantly generates deleterious impurities,such as double-stranded RNAs,that can exacerbate the downstream purification burden and engender safety concerns.The aim of this study was to engineer T7 RNAP thermostability for high-temperature IVT to reduce the dsRNA.The web server PROSS was utilized to predict thermostable mutation sites from the intermediate and elongation structure of T7 RNAP.Through systematic evaluation of individual mutation sites followed by greedy-accumulation optimization of multi-site combinatorial mutants,we successfully overcame the inherent activity-stability trade-off during the evolution and obtained a thermostable variant,M10(Tm:49.5℃),which exhibits robust catalytic activity at elevated temperatures and significantly reduced dsRNA byproduct formation.Structural analysis using homology modelling and molecular dynamics(MD)simulation revealed that the accumulated mutations increased the local rigidity of T7 RNAP with a compacted conformation,enhanced the helical propensity,and allowed the formation of new salt bridges.The enhanced mutant has the potential to act as an effective biocatalyst for high-temperature IVT,adding in high-quality mRNA production,which is a prerequisite for optimizing the downstream purification processes and improving the clinical viability of such therapeutic agents. 展开更多
关键词 T7 RNAP In vitro transcription Thermostability mRNA therapeutics dsRNA
Efficient stereoselective hydroxylation of deoxycholic acid by the robust whole-cell cytochrome P450 CYP107D1 biocatalyst 认领 引用 被引量：2
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作者 Chixiang Sun Baodong Hu +6 位作者 Yanchun Li Zhimeng Wu Jingwen Zhou Jianghua Li Jian Chen Guocheng Du Xinrui Zhao 《Synthetic and Systems Biotechnology》 SCIE CSCD 2023年第4期741-748,共8页
Deoxycholic acid(DCA)has been authorized by the Federal Drug Agency for cosmetic reduction of redundant submental fat.The hydroxylated product(6β-OH DCA)was developed to improve the solubility and pharmaceutic proper... Deoxycholic acid(DCA)has been authorized by the Federal Drug Agency for cosmetic reduction of redundant submental fat.The hydroxylated product(6β-OH DCA)was developed to improve the solubility and pharmaceutic properties of DCA for further applications.Herein,a combinatorial catalytic strategy was applied to construct a powerful Cytochrome P450 biocatalyst(CYP107D1,OleP)to convert DCA to 6β-OH DCA.Firstly,the weak expression of OleP was significantly improved using pRSFDuet-1 plasmid in the E.coli C41(DE3)strain.Next,the supply of heme was enhanced by the moderate overexpression of crucial genes in the heme biosynthetic pathway.In addition,a new biosensor was developed to select the appropriate redox partner.Furthermore,a cost-effective whole-cell catalytic system was constructed,resulting in the highest reported conversion rate of 6β-OH DCA(from 4.8%to 99.1%).The combinatorial catalytic strategies applied in this study provide an efficient method to synthesize high-value-added hydroxylated compounds by P450s. 展开更多
关键词 OleP Deoxycholic acid Hydroxylation Redox partners Whole-cell catalysis
Constitutive expression of codon optimized Trichoderma reesei TrCel5A in Pichia pastoris using GAP promoter 认领 引用
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作者 Yun Hu Renhui Bai +5 位作者 Shaohua Dou Zhimeng Wu Ali Abdulkhani Mohammad Ali Asadollahi Abd El-Fatah Abomohra Fubao Sun 《Systems Microbiology and Biomanufacturing》 2022年第3期498-506,共9页
To address the deficient activity of TrCel5A in naturally secreted cellulase preparation,this study used the GAP promoter to induce constitutive expression of Trichoderma reesei TrCel5A in Pichia pastoris.A recombinan... To address the deficient activity of TrCel5A in naturally secreted cellulase preparation,this study used the GAP promoter to induce constitutive expression of Trichoderma reesei TrCel5A in Pichia pastoris.A recombinant TrCel5A was screened out after gene optimization,synthesis,and expression.The biochemical and enzymatic properties of the new recombinant were characterized.As a result,optimization of shake-flask fermentation of the recombinant was obtained at 28℃,2%inoculum volume,an initial pH of 6.0,as well as glycerol and Tween-80 additions of 30 g/L and 6 g/L,respectively.Under the above-optimized conditions,the recombinant produced 14.8 U/mL of the enzyme activity at 96 h of fermentation.To further enhance enzyme production,pilot-scale cultivation was evaluated using 5-L bioreactors.Using high-cell-density fermentation,the recombinant strain increased enzyme activity to 130.4 U/ml and protein content to 2.49 g/L.In addition,the kinetic factors,including Km and Vmax values for TrCel5A,were detected to be 5.1 mg/mL and 265.9μmol/(min.mg),respectively.Thus,TrCel5A was effectively expressed in P.pastoris under the GAP promoter,and it demonstrated its potential in commercially relevant enzyme hydrolysis of lignocellulosic biomass. 展开更多
关键词 Trichoderma reesei endoglucanase(Cel5A) Pichia pastoris GAP promoter Constitutive expression Fermentation optimization CMC enzyme activity
Optimizing the binding of OGT and a peptidic substrate towards pseudo‑substrate inhibitors via molecular dynamic simulations 认领 引用 被引量：1
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作者 Xinfang Qin Jie Shi +5 位作者 Xia Li Mingming Lu Yating Zhu Qiyuan Yang Zhimeng Wu Cheng Lu 《Systems Microbiology and Biomanufacturing》 EI 2024年第1期165-174,共10页
Elevated O-GlcNAcylation has been shown to be closely correlated with the occurrence and development of cancer,and inhibiting O-GlcNAc transferase(OGT)activity was demonstrated as a potential tumor treatment strategy.... Elevated O-GlcNAcylation has been shown to be closely correlated with the occurrence and development of cancer,and inhibiting O-GlcNAc transferase(OGT)activity was demonstrated as a potential tumor treatment strategy.However,the development of pharmacological OGT inhibitors still faces challenges,such as low affinity and poor selectivity.Consider-ing to OGT preferences for the sequence of its peptidic substrates,we herein integrated molecular dynamics simulation approaches to give deep insights into the binding behaviors between OGT and its peptidic substrate ZO3S1,and discussed the unfavorable inter-residue contacts inside the binding pocket,especially between H509 of OGT and S15 of the peptide,upon temperature increase.Removing this unfavorable contact from the peptide(ZO3S1 with S15A mutation)was shown to be able to increase its interaction with OGT,which was manifested by the enhanced OGT activity against this peptide.The pseudo-substrate peptide(ZO3S1 with S13A and S15A mutations)inhibited the activity of purified OGT with an IC50of 192.9μM and it can also inhibit the total O-GlcNAcylation in cancer cell lines in a concentration-dependent manner.Our results provided useful models and basis for further rational optimization of selective OGT inhibitors based on the dynamic interactions of OGT and its peptidic substrates. 展开更多
关键词 OGT O-GlcNAcylation Peptidic substrates Molecular dynamics simulation Inhibitors
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