JOURNAL OF CHROMATOGRAPHY A
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2021
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IF 4.759
Zhuoting Liu,Chunling Wang,Xu Wang,Ann Van Schepdael
Indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to play an important role in the immune escape process of tumors, and therefore is considered as a promising target for tumor immunotherapy. In this study, off-line and on-line capillary electrophoresis methods were developed for IDO1 inhibitors screening from natural product extracts. The optimized separation conditions of CE were achieved with 32 mM sodium tetraborate (pH 9.22) as background electrolyte, using a separation voltage of 21 kV. The off-line CE method was verified by the determination of enzymatic kinetic parameters and inhibitory mechanisms of two known inhibitors. A partial filling on-line CE method combined with rapid polarity switching was used for rapid screening of IDO1 inhibitors. The whole reaction and separation process was completed within 5 min. The on-line CE screening results showed that six of 18 natural products had inhibitory effect on IDO1, namely Carthamus tinctorius, Schisandra chinensis , Raisin, Coffee, Hawthorn and Radix angelicae sinensis. The results of on-line CE experiments were consistent with the off-line results, which proved the practicability and effectiveness of the method for inhibitors screening.
研究领域:
生物化学
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药物化学
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肿瘤学
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DOI
PubMed
高影响因子
Future Medicinal Chemistry
·
2021
·Vol. 13
·期 13
·
IF 3.808
Xin Lu,Yijun Liu,Nan Qin,Hongyu Yang,Yuting Qiao,Xueyang Jiang,Yao Chen,Feng Feng,Wenyuan Liu,You Zhou,Haopeng Sun
Background: Alzheimer's disease is a multifactorial neurological disorder seen in elderly people. Loss of cholinergic transmission and unbalanced tryptophan metabolism kynurenine pathway have been demonstrated in neuropsychiatric diseases. Methods & results: Among the two series of synthesized compounds, compounds 5c and 5h were identified as effective dual BChE/IDO1 inhibitors, with well-balanced micromolar activity. Compounds 5c and 5h exhibited promising ability to ameliorate behavioral impairment by Morris water maze. The safety of miconazole analogs was also validated by PC12 and SH-SY5Y cell lines. Conclusion: These results highlight the ability of 5c and 5h to treat Alzheimer's disease.
研究领域:
神经科学
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药物化学
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老年医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Hou Xi-xi,Gong Xiao-qing,Mao Long-fei,Sun Ge,Yang Jian-xue
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC50 = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models.
研究领域:
药理学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
Applied Materials Today
·
2022
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IF 8.663
Jiulong Zhang,Xiaoyan Sun,Lin Liu,Xiufeng Zhao,Chunrong Yang,Kexin Li,Haiyang Hu,Mingxi Qiao,Dawei Chen,Xiuli Zhao
Increase extracellular adenosine triphosphate (ATP, a necessary eat me signal for ICD) is a facile way to amplify immunogenic cell death (ICD) cascade for cancer immunotherapy. However, it is still challenging for intratumoral delivery ATP due to complicated enzyme environment in the whole body. Furthermore, tumor immunosuppressive microenvironment (TIM) also hampers the function of mature DCs and limit the activation of immune response. To overcome these drawbacks, a tumor-permeated ATP-based immunogenic cell death amplifier (NABP@SNCs) is fabricated for the first time. (Phenylboronic acid-polyethylene glycol-phenylboronic acid) PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles (ABP) is constructed and interacted with ATP through borate ester bond. Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 and ABP are co-wrapped with MMP-2 sensitive framework to form NABP@SNCs. NABP@SNCs can not only protect ATP degradation but also release small sized ABP under MMP-2 microenvironment for tumor penetration. Interestingly, ATP can also be released into extracellular regions in tumor acidic pH and act as ‘eat me signal’ for DCs maturation. Synergistically ICD activation by BP (PBA-PEG-PBA stabilized ultrasmall platinum nanoparticles) and TIM reversal by NLG919 can facilitate T lymphocyte cells infiltration for immune response. NABP@SNCs can significantly regress tumor growth and reduce pulmonary metastasis for improved cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Xu Gui-Qing,Gong Xiao-Qing,Zhu Ying-Ying,Yao Xiao-Jun,Peng Li-Zeng,Sun Ge,Yang Jian-Xue,Mao Long-Fei
Indoleamine 2,3-dioxygenase 1 (IDO1) plays a predominant role in cancer immunotherapy which catalyzes the initial and rate limiting steps of the kynurenine pathway as a key enzyme. To explore novel IDO1 inhibitors, five derivatives of erlotinib-linked 1,2,3-triazole compounds were designed by using a structure-based drug design strategy. Drug-target interactions (DTI) were predicted by DeePurpose, an easy-to-use deep learning library that contains more than 50 algorithms. The DTI prediction results suggested that the designed molecules have potential inhibitory activities for IDO1. Chemical syntheses and bioassays showed that the compounds exhibited remarkable inhibitory activities against IDO1, among them, compound e was the most potent with an IC50 value of 0.32 ± 0.07 μM in the Hela cell assay. The docking model and ADME analysis exhibited that the effective interactions of these compounds with heme iron and better drug-likeness ensured the IDO1 inhibitory activities. The studies suggested that compound e was a novel and interesting IDO1 inhibitor for further development.
研究领域:
癌症研究
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药物化学
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药物设计
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-20
·
IF 14.7
Liu Jinhu,Zhao Huajun,Gao Tong,Huang Xinyan,Liu Shujun,Liu Meichen,Mu Weiwei,Liang Shuang,Fu Shunli,Yuan Shijun,Yang Qinglin,Gu Panpan,Li Nan,Ma Qingping,Liu Jie,Zhang Xinke,Zhang Na,Liu Yongjun
Cytotherapy is a strategy to deliver modified cells to a diseased tissue, but targeting solid tumours remains challenging. Here we design macrophages, harbouring a surface glypican-3-targeting peptide and carrying a cargo to combat solid tumours. The anchored targeting peptide facilitates tumour cell recognition by the engineered macrophages, thus enhancing specific targeting and phagocytosis of tumour cells expressing glypican-3. These macrophages carry a cargo of the TLR7/TLR8 agonist R848 and INCB024360, a selective indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, wrapped in C16-ceramide-fused outer membrane vesicles (OMV) of Escherichia coli origin (RILO). The OMVs facilitate internalization through caveolin-mediated endocytosis, and to maintain a suitable nanostructure, C16-ceramide induces membrane invagination and exosome generation, leading to the release of cargo-packed RILOs through exosomes. RILO-loaded macrophages exert therapeutic efficacy in mice bearing H22 hepatocellular carcinomas, which express high levels of glypican-3. Overall, we lay down the proof of principle for a cytotherapeutic strategy to target solid tumours and could complement conventional treatment.
研究领域:
肿瘤学
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免疫治疗
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Zhe Li,Xiao-Meng Liu,Fei Tan,Jia-Qian Wang,Xin Qiao,Yu-Kuan Feng,Jing-Yuan Xu,Ji-Hui Hao
Convincing evidence revealed that some platinum-based drugs could stimulate immunological recognition, thereby inducing immunogenic cell death (ICD). Indoleamine-2,3-dioxygenase (IDO) is overexpressed in tumors, which caused exhaustion of tryptophan (T-cell energy) and constructed an immunosuppressive tumor microenvironment. Herein, considering IDO inhibition to improve chemotherapy, a series of IDOi-Pt(IV) prodrugs were designed to not only target DNA and IDO but also facilitate tumor-antigen exposure and immunomodulation. The optimal IDOi-Pt(IV) prodrugs (named compound 10) significantly enhanced intracellular accumulation 22.4-fold and cytotoxicity 61.75-fold superior to cisplatin in HeLa cells. Moreover, immunofluorescence and enzyme-linked immunosorbent assays revealed that 10 induced reactive oxygen species-mediated endoplasmic reticulum stress and secretion of damage-associated molecular patterns, thereby presenting ICD effects. Molecular docking, enzyme inhibition, and Western blot assays demonstrated that 10 could effectively inhibit IDO1 and reverse immunosuppression, as further verified by mixed leukocyte reactions. In vivo tests showed that 10 exhibited high-efficiency and low-toxicity antitumor effects compared to cisplatin, presenting successful chemoimmunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2021
·
IF 9.229
Ziyuan Huang,Yuying Chen,Jiulong Zhang,Wenpan Li,Menghao Shi,Mingxi Qiao,Xiuli Zhao,Haiyang Hu,Dawei Chen
There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.
研究领域:
癌症研究
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纳米技术
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免疫治疗
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）