NPJ drug discovery最新文献_第9页

Mechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells. 一种新型双功能Gag-Pol二聚体增强CARD8炎性体激活和清除hiv感染细胞的机制基础。

NPJ drug discovery Pub Date : 2025-01-01 Epub Date: 2025-09-01 DOI: 10.1038/s44386-025-00025-2

Klarissa Hollander, Swapnil C Devarkar, Su Tang, Ritudhwaj Tiwari, Shumeng Ma, Won Gil Lee, Elizabeth Denn, Qiankun Wang, Krasimir A Spasov, Jake A Robbins, Kathleen M Frey, William L Jorgensen, Yong Xiong, Liang Shan, Karen S Anderson

{"title":"Mechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells.","authors":"Klarissa Hollander, Swapnil C Devarkar, Su Tang, Ritudhwaj Tiwari, Shumeng Ma, Won Gil Lee, Elizabeth Denn, Qiankun Wang, Krasimir A Spasov, Jake A Robbins, Kathleen M Frey, William L Jorgensen, Yong Xiong, Liang Shan, Karen S Anderson","doi":"10.1038/s44386-025-00025-2","DOIUrl":"10.1038/s44386-025-00025-2","url":null,"abstract":"A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These NNRTIs stimulate dimerization of the Gag-Pol polyprotein, resulting in premature HIV-1 protease (PR) dimerization and cleavage of intracellular CARD8. A unique cell-based high-throughput screen was developed to identify potent compounds activating the CARD8 inflammasome through Gag-Pol dimerization. Our in-house library of NNRTIs was evaluated, including a series of catechol diethers, which are potent, nontoxic antivirals. JLJ648 was identified as a promising dual-function antiviral and Gag-Pol dimerizer. Cryo-EM studies of HIV reverse transcriptase p66 bound to JLJ648 revealed populations of homodimers and, surprisingly, a homotetramer. This novel homotetramer structure resembling an 'infinity knot' revealed two JLJ648-bound homodimers forming an extensive interface and nucleated around a dimer of JLJ648 molecules. Structure-guided mutagenesis studies indicate that Gag-Pol homotetramerization may play a critical role in facilitating PR self-cleavage and triggering pyroptosis.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"22"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12401731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer's disease mice. 发现一种小分子分泌的簇蛋白增强剂，可以改善阿尔茨海默病小鼠的记忆。

NPJ drug discovery Pub Date : 2025-01-01 Epub Date: 2025-05-02 DOI: 10.1038/s44386-025-00009-2

Whitaker Cohn, Jesus Campagna, Dongwook Wi, Jessica T Lee, Sahiba Beniwal, Gazmend Elezi, Chunni Zhu, Barbara Jagodzinska, Julian Whitelegge, Robert Damoiseaux, Varghese John

{"title":"Discovery of a small molecule secreted clusterin enhancer that improves memory in Alzheimer's disease mice.","authors":"Whitaker Cohn, Jesus Campagna, Dongwook Wi, Jessica T Lee, Sahiba Beniwal, Gazmend Elezi, Chunni Zhu, Barbara Jagodzinska, Julian Whitelegge, Robert Damoiseaux, Varghese John","doi":"10.1038/s44386-025-00009-2","DOIUrl":"10.1038/s44386-025-00009-2","url":null,"abstract":"Despite substantial research and drug discovery efforts, Alzheimer's Disease (AD) remains the sixth leading cause of death in the United States, underscoring the urgent need for novel therapeutic targets. A mutation in the clusterin (CLU) gene that hinders expression of the cyto-protective secreted isoform of clusterin (sCLU) that affects the aggregation and clearance of two key proteins implicated in AD, Aβ and tau, is the third most significant genetic risk factor for late-onset AD. Here, we present findings from our drug discovery program to identify small molecules that enhance sCLU levels and assess their impact on AD pathology and cognition in a murine model of AD. A high-throughput screening campaign identified two classes of epigenetic modulators that increase sCLU levels with subsequent medicinal chemistry efforts leading to bromodomain and extra-terminal (BET) inhibitor new chemical entities (NCEs) with enhanced potency, drug-like properties, and oral brain bioavailability. The lead candidate NCE, DDL-357, increased brain sCLU in the murine ApoE4TR-5XFAD model of AD in a subchronic study. In a follow-up chronic study in the murine 3xTg-AD model, DDL-357 reduced phospho-tau in brain and led to improvements in mouse performance and memory in the Barnes maze testing paradigm. Proteomic analysis of brain tissue from both AD models revealed changes in proteins involved in mitochondrial function and synaptic plasticity. These findings reveal the potential of sCLU enhancement as a target for therapeutic development in AD and support the continued development of the preclinical lead candidate.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"2 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AI meets physics in computational structure-based drug discovery for GPCRs. 人工智能在基于计算结构的gpcr药物发现中与物理学相结合。

NPJ drug discovery Pub Date : 2025-01-01 Epub Date: 2025-07-03 DOI: 10.1038/s44386-025-00019-0

Mayako Michino, Jeremie Vendome, Irina Kufareva

引用次数: 0

Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity. 调节肿瘤免疫的选择性ITK抑制剂索奎替尼的合成和表征。

NPJ drug discovery Pub Date : 2024-12-04 DOI: 10.1038/s44386-024-00002-1

Lih-Yun Hsu, James T Rosenbaum, Erik Verner, William B Jones, Craig M Hill, James W Janc, Joseph J Buggy, Rahul D Pawar, Poorva Ghosh, Dan Li, Ning Ding, John C Reneau, Michael S Khodadoust, Youn H Kim, Ryan A Wilcox, Richard A Miller

{"title":"Synthesis and characterization of soquelitinib a selective ITK inhibitor that modulates tumor immunity.","authors":"Lih-Yun Hsu, James T Rosenbaum, Erik Verner, William B Jones, Craig M Hill, James W Janc, Joseph J Buggy, Rahul D Pawar, Poorva Ghosh, Dan Li, Ning Ding, John C Reneau, Michael S Khodadoust, Youn H Kim, Ryan A Wilcox, Richard A Miller","doi":"10.1038/s44386-024-00002-1","DOIUrl":"10.1038/s44386-024-00002-1","url":null,"abstract":"ITK is a kinase involved in T cell activation, proliferation and differentiation. In mice, selective knock-out of the ITK gene produces Th1 skewing of T helper cell differentiation. Soquelitinib, a covalent ITK inhibitor, blocks ITK activity with greater than 100-fold selectivity compared to inhibition of a related kinase, RLK. We describe the chemistry and biologic effects of soquelitinib. In vitro studies with normal or malignant T cells demonstrated that soquelitinib suppresses Th2 cytokine production preferentially with relative sparing of Th1 cytokines. Soquelitinib inhibits the in vivo growth of several syngeneic murine tumors including those that do not express ITK. Treatment with soquelitinib leads to increased tumor infiltration of normal CD8+ cells that possess enhanced T effector function. Soquelitinib reduced expression of T cell exhaustion markers and was able to restore T effector function to exhausted cells. Pharmacologic selective ITK inhibition may represent a novel approach to cancer immunotherapy.","PeriodicalId":520448,"journal":{"name":"NPJ drug discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148364729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure and dynamics in drug discovery. 药物发现中的结构和动力学。

NPJ drug discovery Pub Date : 2024-11-07 DOI: 10.1038/s44386-024-00001-2

Haixin Wei, J Andrew McCammon

引用次数: 0