BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2013
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IF 3.848
Wu Lian,Mingyi Wu,Ning Huang,Na Gao,Chuang Xiao,Zi Li,Zhigang Zhang,Yongtang Zheng,Wenlie Peng,Jinhua Zhao
Background Fucosylated glycosaminoglycan (FG) is a novel glycosaminoglycan with a chondroitin sulfate-like backbone and fucose sulfate branches. The aim of this study is to investigate the mechanism and structure–activity relationships (SAR) of FG for combating HIV-1 infection. Methods Anti-HIV activities of FGs were assessed by a cytopathic effect assay and an HIV-1 p24 detection assay. The biomolecule interactions were explored via biolayer interferometry technology. The SAR was established by comparing its anti-HIV-1 activities, conserved CD4 induced (CD4i) epitope-dependent interactions and anticoagulant activities. Results FG efficiently and selectively inhibited the X4- and R5X4-tropic HIV-1 infections in C8166 cells with little cytotoxicity against C8166 cells and PBMCs. Our data indicated that FG bound to gp120 with nanomolar affinity and may interact with CD4i of gp120. Additionally, the CD4i binding affinity of FG was higher than that of dextran sulfate. SAR studies suggested that the unique sulfated fucose branches account for the anti-HIV-1 activity. The molecular size and present carboxyl groups of FG may also play important roles in various activities. Notably, several FG derivatives showed higher anti-HIV-1 activities and much lower anticoagulant activities than those of heparin. Conclusions FG exhibits strong activity against X4- and R5X4-tropic HIV-1 infections. The mechanism may be related to targeting CD4i of gp120, which results in inhibition of HIV-1 entry. The carboxyl group substituted derivatives of FG (8.5–12.8 kDa), might display high anti-HIV-1 activity and low anticoagulant activity. General significance Our data supports further the investigation of FG derivatives as novel HIV-1 entry inhibitors targeting CD4i.
研究领域:
病毒学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MACROMOLECULAR RESEARCH
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2012
·Vol. 20
·期 4
·358-365
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IF 1.153
Zeng Rong,Wang Zehu,Wang Hongran,Chen Liqiang,Yang Lin,Qiao Renzhong,Hu Liming,Li Zelin
Two kinds of chitosan-stavudine (d4T) conjugates, chitosan- O -isopropyl-5′- O -d4T monophosphate conjugate (Cs-P-d4T) with a phosphoramide linkage and chitosan-5′- O -succinyl-d4T conjugate (Cs-S-d4T) with a succinic spacer, were synthesized using an Atherton-Todd reaction and carbodiimide coupling reaction, respectively, and then structurally characterized. Their in vitro drug release behaviors and anti-human immunodeficiency virus (HIV) activity were investigated and compared. Both of the chitosan-d4T conjugates more strongly prefer to release corresponding d4T derivatives rather than free d4T in a prolonged manner but have different hydrolysis routes. The anti-HIV activity and cytotoxicity evaluated in the MT4 cell line revealed that the anti-HIV selectivity index was in the following order: Cs-P-d4T > d4T >> Cs-S-d4T since the released d4T-5′-( O -isopropyl) monophosphate from Cs-P-d4T can bypass the rate-limiting bottleneck of nucleoside phosphorylation, while the released 5′- O -succinyl-d4T from Cs-S-d4T has to be hydrolyzed to d4T and then successively phosphorylated to its active form to exert antiviral activity. The results suggested that constructing a chitosan-nucleoside reverse transcriptase inhibitor (NRTI) conjugate with a phosphoramide linkage may be an efficient approach for improving NRTI therapy efficacy in antiretroviral treatment.
研究领域:
药学
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生物化学
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抗病毒研究
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DOI
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2014
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IF 2.736
Ling Li,Jin Zhang,Chao Li,Liqiang Chen,Renzhong Qiao
To efficiently deliver stavudine (d4T) for AIDS therapy, chitosan–stavudine conjugate (Cs–d4T) was synthesized. However, its poor water-solubility limited its clinical application. In this study, a sulphonated chitosan–stavudine conjugate (SCs–d4T) was synthesized with a mild SO 3 ·Py complex sulphonation strategy. Chemical characteristics and morphology of Cs–d4T and SCs–d4T were performed by NMR, XRD, FTIR, ICP-AES and SEM. SCs–d4T demonstrated satisfactory solubility (106-bold of Cs–d4T solubility), good anti-HIV activity (6-fold of d4T anti-HIV activity), and well sustained release ability. The major release product O -isopropyl-5′- H -phosphonate of d4T (d4T-P-H) showed higher anti-HIV activity than d4T. For further evaluating the influence of linker and sulphonation strategy on anti-HIV activity, chitosan grafted with d4T by succinyl linker (Cs–sd4T) and SCs–d4T sulphonated by oleum were also prepared. The result showed that the O -isopropyl monophosphate linker of Cs–d4T and SO 3 ·Py complex sulphonation strategy revealed higher anti-HIV activity than succinyl linker of Cs–sd4T and oleum sulphonation strategy, respectively.
研究领域:
药学
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生物医学工程
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DOI
PubMed
高影响因子
ACS Synthetic Biology
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2024
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IF 3.7
Mei Tang,Xianhao Xu,Yanfeng Liu,Jianghua Li,Guocheng Du,Xueqin Lv,Long Liu
Betulinic acid (BA) is a lupane-type triterpenoid with potent anticancer and anti-HIV activities. Its great potential in clinical applications necessitates the development of an efficient strategy for BA synthesis. This study attempted to achieve efficient BA biosynthesis in Saccharomyces cerevisiae using systematic metabolic engineering strategies. First, a de novo BA biosynthesis pathway in S. cerevisiae was constructed, which yielded a titer of 14.01 ± 0.21 mg/L. Then, by enhancing the BA synthesis pathway and dynamic inhibition of the competitive pathway, a greater proportion of the metabolic flow was directed toward BA synthesis, achieving a titer of 88.07 ± 5.83 mg/L. Next, acetyl-CoA and NADPH supply was enhanced, which increased the BA titer to 166.43 ± 1.83 mg/L. Finally, another BA synthesis pathway in the peroxisome was constructed. Dual regulation of the peroxisome and cytoplasmic metabolism increased the BA titer to 210.88 ± 4.76 mg/L. Following fed-batch fermentation process modification, the BA titer reached 682.29 ± 8.16 mg/L. Overall, this work offers a guide for building microbial cell factories that are capable of producing terpenoids with efficiency.
研究领域:
生物技术
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代谢工程
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药学
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微生物学
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DOI
PubMed
高影响因子
Communications Biology
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2023
·Vol. 6
·期 1
·1-12
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IF 5.9
Wang You-Yuan,Zhen Cheng,Hu Wei,Huang Hui-Huang,Li Yan-Jun,Zhou Ming-Ju,Li Jing,Fu Yu-Long,Zhang Peng,Li Xiao-Yu,Yang Tao,Song Jin-Wen,Fan Xing,Zou Jun,Meng Si-Run,Qin Ya-Qin,Jiao Yan-Mei,Xu Ruonan,Zhang Ji-Yuan,Zhou Chun-Bao,Yuan Jin-Hong,Huang Lei,Shi Ming,Cheng Liang,Wang Fu-Sheng,Zhang Chao
CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.
研究领域:
免疫学
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病毒学
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代谢学
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HIV/AIDS研究
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DOI
PubMed
高影响因子
Frontiers in Plant Science
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2017
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IF 4.291
Su Ping,Guan Hongyu,Zhang Yifeng,Wang Xing,Gao Linhui,Zhao Yujun,Hu Tianyuan,Zhou Jiawei,Ma Baowei,Tu Lichan,Tong Yuru,Huang Luqi,Gao Wei
Tripterygium wilfordii produces not only ent-kaurene, which is an intermediate of gibberellin (GA) biosynthesis in flowering plants, but also 16α-hydroxy-ent-kaurane, whose physiological role has not been characterized. The two compounds are biosynthesized from the universal diterpenoid precursor (E,E,E)-geranylgeranyl diphosphate (GGPP) by diterpene synthases, which have been discovered and functionally characterized in T. wilfordii. Here, we described the functional characterization of four cytochrome P450 reductases (TwCPR) and one ent-kaurene oxidase (TwKO). Four TwCPRs were found to have relatively ubiquitous expression in T. wilfordii root, stem, leaf, and flower tissues. Co-expression of both a TwCPR and TwKO in yeast showed that TwCPR3 has a slightly better activity for providing the electrons required for these reactions, indicating that TwCPR3 is more suitable for use in the functional analysis of other cytochrome P450 monooxygenases. TwKO catalyzed the three-step oxidation of the C4α methyl of the tetracyclic diterpene intermediate ent-kaurene to form ent-kaurenoic acid as an early step in GA biosynthesis. Notably, TwKO could also convert 16α-hydroxy-ent-kaurane to 16α-hydroxy-ent-kaurenoic acid, indicating an important function of 16α-hydroxy-ent-kaurane in the anti-HIV principle tripterifordin biosynthetic pathway in planta. Homology modeling and molecular docking were used to investigate the unknown crucial active amino acid residue involved in the catalytic reaction of TwKO, and one key residue (Leu387) contributed to the formation of 16α-hydroxy-ent-kaurenoic acid, most likely by forming hydrogen bonds with the hydroxyl group (-OH) of 16α-hydroxy-ent-kaurane, which laid the basis for further investigation of the multifunctional nature of KO catalysis. Also, our findings paved the way for the complete biosynthesis of the anti-HIV principle tripterifordin.
研究领域:
植物生物化学
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酶学
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分子生物学
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生药学
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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
Yan Liu,Yuetao Zhang,Zijie Li,Zhiqi Li,Shaoke Zhou,Yong Xia,Lei Mou
Rapid, accurate, and cost-effective strategies for the multiplexed and quantitative detection of multiple infectious disease biomarkers are still lack in hospital. Here, we introduce a multiplexed screen-printed electrode for the simultaneous detection of three infectious disease biomarkers: HBsAg, anti-HIV, and anti-TP. The electrode modified with in-situ deposition of gold nanoparticles (AuNPs) and MXene multilayered nanosheets. Comprehensive characterization confirms the morphology and electrochemical response of the AuNPs&MXene modified screen-printed electrode (AuNPs&MXene-SPE). AuNPs&MXene composite contributes to enhance sensitivity by maximizing surface area and improving electron transfer efficiency. The AuNPs&MXene-SPE exhibits outstanding detection performance for HBsAg, anti-HIV, and anti-TP. The AuNPs&MXene-SPE sensors achieve broad detection ranges (0.05–1000 ng/mL for HBsAg, 0.35–140 ng/mL for anti-HIV, and 0.25–100 ng/mL for anti-TP) accompanied by low limits of detection (0.01, 0.11, and 0.10 ng/mL, respectively). Applied to standard serum samples, the sensors showcase precision with relative standard deviations consistently below 5.0 %, affirming their suitability for complex solution environments. These sensors offer notable advantages, including cost-effectiveness, rapid response, high sensitivity, and specificity, eliminating the necessity for expensive equipment, which open avenues for the realization of point-of-care testing (POCT).
研究领域:
电化学
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生物传感器
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纳米材料
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传染病
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即时检测
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DOI
高影响因子
危险品化学品经营许可证（带存储）