作者: Fan, Panpan ; Zhao, Qingchun ; Chen, Huanhua ; Lin, Junjie ; Gu, Yujia ; Xu, Zihua ; Zhou, Lijun ; Li, Xinzhu ; Wang, Weiyi ; Zheng, Fangyuan ; Liu, Siyuan ; Yang, Aizhu

Sterol regulatory element binding proteins (SREBPs) are a series of cholesterol-related transcription factors. Their role in regulating brain cholesterol biosynthesis, amyloid accumulation, and tau tangles formation has been intensively studied in protein-protein interaction analysis based on genes in clinical databases. SREBPs play an important role in maintaining cholesterol homeostasis in the brain. There are three subtypes of SREBPs, SREBP-1a stimulates the expression of genes related to cholesterol and fatty acid synthesis, SREBP-1c stimulates adipogenesis, and SREBP-2 stimulates cholesterol synthase and LDL receptors. SREBP-2 is activated in response to cholesterol depletion and stimulates a compensatory upregulation of cholesterol uptake and synthesis. Previous studies have shown that inhibition of SREBP-2 reduces cholesterol and amyloid accumulation, and new research suggests that SREBPs play a multifaceted role in Alzheimer's disease. Here, we highlight the importance of SREBPs in AD, in terms of multiple pathways regulating cholesterol in the brain, and primarily demonstrate the potential of SREBP-2 inhibitors. There was a trend towards a significant increase in the expression levels of different SREBP isoforms in AD patients compared to healthy controls. Therefore, there is a close link between SREBPs and AD, and this review analyses the potential role of SREBPs in the treatment of AD. In addition, we systematically reviewed the research progress of SREBPs in AD, and this review will provide more innovative insights into the pathogenesis and treatment of AD and new strategies for drug development in AD.

2023-07-03·Expert Opinion on Investigational Drugs

Psoriasis: a focus on upcoming oral formulations

Review

作者: Puig, Lluís ; Carmona-Rocha, Elena ; Rusiñol, Lluís

INTRODUCTIONTargeted therapies have greatly improved the quality of life of patients with psoriasis. Despite the extensive list of treatments available, multiple new drugs are being developed, especially oral therapies with potential advantages as regards comfort of administration. However, the efficacy and safety of these new oral therapies need to be improved to match those of novel biologics.AREAS COVEREDWe provide a narrative review of the oral therapies for psoriasis that are currently under development, from Jak inhibitors to oral IL-17 and IL-23 inhibitors, among others. A literature search was performed for articles published from 1 January 2020, to 6 June 2023.EXPERT OPINIONThe approval of deucravacitinib, the first Jak inhibitor for the treatment of moderate-to-severe plaque psoriasis, heralds a bright therapeutic future with multiple new oral formulations. A great number of oral treatments with singular mechanism of action, like A3AR agonists, HSP90 inhibitors, ROCK-2 inhibitors, oral TNF inhibitors, oral IL-23 inhibitors, oral IL-17 inhibitors, PD4 inhibitors (orismilast) and several Tyk2 inhibitors, are currently being evaluated in clinical trials and could be suitable for approval in the future. Growing variation in treatment modes of administration will allow dermatologists to better integrate patient preferences in the therapeutic decision process.

Chemoproteomics identifies proteoform-selective caspase-2 inhibitors

作者: Boatner, Lisa M. ; Tran, Ky ; Desai, Heta S. ; Backus, Keriann M. ; Faragalla, Marina ; Armenta, Ernest ; Yan, Tianyang ; Burton, Nikolas ; Takayoshi, Evan E. ; Zhou, Annie ; Ofori, Samuel ; Castellón, José O. ; Shek, Jeremy

ABSTRACTCaspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all twelve human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive non-catalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and atobacco etch virus(TEV) protease activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2. Focused analogue synthesis combined with chemoproteomic target engagement analysis in cellular lysates and in cells yielded both pan-caspase reactive molecules and caspase-2 selective lead compounds together with a structurally matched inactive control. Application of this focused set of tool compounds to stratify caspase contributions to initiation of intrinsic apoptosis, supports compensatory caspase-9 activity in the context of caspase-2 inactivation. More broadly, our study highlights future opportunities for the development of proteoform-selective caspase inhibitors that target non-conserved and non-catalytic cysteine residues.

100 项与 Caspase-2抑制剂(Elgia) 相关的药物交易

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