更新于：2024-11-01

TYMS x APP

更新于：2024-11-01

基本信息

关联

项与 TYMS x APP 相关的药物

Fol-PRI-002

靶点

APP x TYMS

作用机制

APP抑制剂 [+1]

在研机构

Priavoid GmbH

原研机构

Priavoid GmbH

在研适应症

阿尔茨海默症

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TYMS x APP 相关的临床结果

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100 项与 TYMS x APP 相关的转化医学

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0 项与 TYMS x APP 相关的专利（医药）

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项与 TYMS x APP 相关的文献（医药）

2023-01-01·Frontiers in immunology

Identification of berberine as a potential therapeutic strategy for kidney clear cell carcinoma and COVID-19 based on analysis of large-scale datasets.

Article

作者: Li, Xiushen ; Zheng, Yihou ; Wang, Xiaoyu ; Nie, Kechao ; Yang, Fuxia ; Zheng, Zhihua ; Zheng, Kairi ; Liang, Wencong

BackgroundRegarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19.MethodsBased on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated.ResultsIn total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins.ConclusionThis study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.

2018-11-27·Biological Chemistry

An alternative processing pathway of APP reveals two distinct cleavage modes for rhomboid protease RHBDL4

Article

作者: Recinto, Sherilyn Junelle ; Munter, Lisa Marie ; Paschkowsky, Sandra

AbstractSince the first genetic description of a rhomboid in Drosophila melanogaster, tremendous efforts have been geared towards elucidating the proteolytic mechanism of this particular class of intramembrane proteases. In particular, mammalian rhomboid proteases sparked our interest and we aimed to investigate the human homologue RHBDL4. In light of our recent finding of the amyloid precursor protein (APP) family as efficient substrates of RHBDL4, we were enticed to further study the specific proteolytic mechanism of this enzyme by comparing cleavage patterns of wild type APP and APP TMS chimeras. Here, we demonstrate that the introduction of positively charged amino acid residues in the TMS redirects the RHBDL4-mediated cleavage of APP from its ectodomain closer towards the TMS, possibly inducing an ER-associated degradation (ERAD) of the substrate. In addition, we concluded that the cytoplasmic tail and proposed palmitoylation sites in the ectodomain of APP are not essential for the RHBDL4-mediated APP processing. In summary, our previously identified APP ectodomain cleavages by RHBDL4 are a subsidiary mechanism to the proposed RHBDL4-mediated ERAD of substrates likely through a single cleavage near or within the TMS.

2010-08-17·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization

1区 · 综合性期刊

Article

作者: Munter, Lisa-Marie ; Beyermann, Michael ; Gust, Ronald ; Hildebrand, Peter W. ; Ness, Julia ; Bulic, Bruno ; Dasari, Muralidhar ; Langosch, Dieter ; Richter, Luise ; Unterreitmeier, Stephanie ; Reif, Bernd ; Multhaup, Gerd ; Weggen, Sascha

Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by γ-secretase result in the release of amyloid-β (Aβ) peptides of variable length. Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer’s disease, as they are believed to initiate neuronal degeneration. Sulindac sulfide, which is known as a potent γ-secretase modulator (GSM), selectively reduces Aβ42 production in favor of shorter Aβ species, such as Aβ38. By studying APP–TMS dimerization we previously showed that an attenuated interaction similarly decreased Aβ42 levels and concomitantly increased Aβ38 levels. However, the precise molecular mechanism by which GSMs modulate Aβ production is still unclear. In this study, using a reporter gene-based dimerization assay, we found that APP–TMS dimers are destabilized by sulindac sulfide and related Aβ42-lowering compounds in a concentration-dependent manner. By surface plasmon resonance analysis and NMR spectroscopy, we show that sulindac sulfide and novel sulindac-derived compounds directly bind to the Aβ sequence. Strikingly, the attenuated APP–TMS interaction by GSMs correlated strongly with Aβ42-lowering activity and binding strength to the Aβ sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP–TMS. We conclude that these GSMs decrease Aβ42 levels by modulating APP–TMS interactions. This effect specifically emphasizes the importance of the dimeric APP–TMS as a promising drug target in Alzheimer’s disease.