作者: Jiang, Zhihong ; Zhang, Wei ; Zhu, Guoyuan ; Huang, Hanlin ; Wang, Raoqiong ; Li, Shuangyang ; Huang, Guoxin ; Yang, Sijin ; Wang, Liang ; Yang, Jinrui

Abstract:

Although the gut microbiota and kynurenine (KYN) metabolism have significant protective effects against ischaemic stroke (IS), the exact mechanism has yet to be fully elucidated. Combined serum metabolomics and 16S rRNA gene sequencing were used to reveal the differences between the gut microbiota and metabolites in rats treated with or without blueberry extract. Faecal microbiota transplantation (FMT) was employed to validate the protective role of the gut microbiota in IS. Furthermore, the interaction between Prevotella and IS was also confirmed in patients. Rats with IS experienced neurological impairments accompanied by an impaired intestinal barrier and disturbed intestinal flora, which further contributed to heightened inflammatory responses. Furthermore, Prevotella played a critical role in IS pathophysiology, and a positive correlation between Prevotella and KYN was detected. The role of KYN metabolism in IS was further demonstrated by the finding that IDO was significantly upregulated and that the use of the IDO inhibitor, attenuated KYN metabolic pathway activity and ameliorated neurological damage in rats with IS. Prevotella intervention also significantly improved stroke symptoms and decreasing KYN levels in rats with IS. FMT showed that the beneficial effects of blueberry extract on IS involve gut bacteria, especially Prevotella, which were confirmed by microbiological analyses conducted on IS patients. Moreover, blueberry extract led to significant changes in kynurenic acid levels and tryptophan and IDO levels through interactions with Prevotella. Our study demonstrates for the first time that blueberry extract could modulate “intestinal microecology‐KYN metabolism” to improve IS.

2024-08-22·JOURNAL OF MEDICINAL CHEMISTRY

Structural Insights into Protein-Inhibitor Interactions in Human Tryptophan Dioxygenase

Article

作者: Yeh, Syun-Ru ; Geeraerts, Zachary ; Ishigami, Izumi ; Frédérick, Raphaël ; Kozlova, Arina ; Pham, Khoa N. ; Mathieu, Caroline ; Lewis-Ballester, Ariel

Human tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two important targets in cancer immunotherapy. Extensive research has led to a large number of potent IDO inhibitors; in addition, 52 structures of IDO in complex with inhibitors with a wide array of chemical scaffolds have been documented. In contrast, progress in the development of TDO inhibitors has been limited. Only four structures of TDO in complex with competitive inhibitors that compete with the substrate L-tryptophan for binding to the active site have been reported to date. Here we systematically evaluated the structures of TDO in complex with competitive inhibitors with three types of pharmacophores, imidazo-isoindole, indole-tetrazole, and indole-benzotriazole. The comparative assessment of the protein-inhibitor interactions sheds new light into the structure-based design of enzyme-selective inhibitors.

2024-08-08·JCI Insight

Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection

Article

作者: Mehra, Smriti ; Dick, Edward J. ; Singh, Bindu ; Shivanna, Vinay ; Sharan, Riti ; Singh, Dhiraj K ; Singh, Dhiraj K. ; Arora, Garima ; Ravichandran, Gayathri ; Hall-Ursone, Shannan ; Kaushal, Deepak ; Alvarez, Xavier ; Escobedo, Ruby ; Dick, Edward J

Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis-specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.

项与 IDO抑制剂(齐鲁制药) 相关的新闻（医药）

2022-11-28

·Business Wire

2022 Bladder Cancer Update Bulletin: Key Opinion Leader (KOL) Views on Recent Developments - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "Bladder Cancer: Update Bulletin #2" newsletter has been added to ResearchAndMarkets.com's offering. This edition presents leading key opinion leader (KOL) views on recent developments in the Bladder Cancer market. Topics covered include: Bristol-Myers Squibb (BMS) presenting positive data from a Phase I/II study investigating a combination of its PD-1 inhibitor Opdivo (nivolumab) with its pipeline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, BMS-986205, in heavily pretreated patients with advanced bladder cancer; BioCanCell announcing final results for its Phase IIb combination trial investigating its lead compound BC-819 in combination with the BCG vaccine in 38 patients with intermediate-and high-risk non-muscle invasive bladder cancer (NMIBC); KOLs offering their updated opinions on the the supply status of the BCG vaccine in the US and key European markets. Business Questions: How do the KOLs perceive the Phase II combination results for BMS' Opdivo with the IDO inhibitor BMS-986205 in patients with advanced bladder cancer? Do KOLs view PD-1/PD-L1 and IDO inhibition as a viable combination approach going forward? What are experts' thoughts on PD-L1 expression and its future use as a biomarker in patients with bladder cancer? Do KOLs hold any other concerns about dual immunotherapy combinations such as cost, access or increased risk of toxicity? If approved, how and when would KOLs consider using the combination approach of Opdivo with an IDO inhibitor? Based on published Phase II data, how do the experts view the results so far for BC-819 with BCG in patients with NMIBC? Are the KOLs enthusiastic about intravesical gene therapies as treatments for NMIBC and if so, why? How do the experts perceive the planned Phase III trial investigating BC-819 in patients that are BCG-recurrent? If approved, can BC-819 gain market share in patients with high-risk or intermediate-risk NMIBC? What are KOLs' opinions on the supply shortages previously reported for the BCG vaccine and are they being addressed? For more information about this newsletter visit https://www.researchandmarkets.com/r/9ke1kl

临床2期疫苗免疫疗法临床结果ASCO会议

100 项与 IDO抑制剂(齐鲁制药) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
免疫系统疾病	临床前	中国	齐鲁制药有限公司	2020-12-25
感染	临床前	中国	齐鲁制药有限公司	2020-12-25
炎症	临床前	中国	齐鲁制药有限公司	2020-12-25
肿瘤	临床前	中国	齐鲁制药有限公司	2020-12-25