预约演示

更新于：2025-05-07

SCAP

更新于：2025-05-07

基本信息

别名

KIAA0199、SCAP、SREBF chaperone

+ [2]

简介

Escort protein required for cholesterol as well as lipid homeostasis (By similarity). Regulates export of the SCAP-SREBP complex from the endoplasmic reticulum to the Golgi upon low cholesterol, thereby regulating the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:26311497). At high sterol concentrations, formation of a ternary complex with INSIG (INSIG1 or INSIG2) leads to mask the ER export signal in SCAP, promoting retention of the complex in the endoplasmic reticulum (By similarity). Low sterol concentrations trigger release of INSIG, a conformational change in the SSD domain of SCAP, unmasking of the ER export signal, promoting recruitment into COPII-coated vesicles and transport of the SCAP-SREBP to the Golgi: in the Golgi, SREBPs are then processed, releasing the transcription factor fragment of SREBPs from the membrane, its import into the nucleus and up-regulation of LDLR, INSIG1 and the mevalonate pathway (PubMed:26311497). Binds cholesterol via its SSD domain (By similarity).

关联

项与 SCAP 相关的药物

UT-59

靶点

SCAP

作用机制

SCAP 抑制剂

在研机构

The University of Texas Southwestern Medical Center

原研机构

The University of Texas Southwestern Medical Center

在研适应症

代谢性疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

CAP-1628987

靶点

SCAP

作用机制

SCAP 抑制剂

在研机构

Capulus Therapeutics LLC [+1]

原研机构

Capulus Therapeutics LLC [+1]

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

SCAP siRNA (Dicerna Pharma)

靶点

SCAP

作用机制

SCAP 调节剂

在研机构

Dicerna Pharmaceuticals, Inc.

原研机构

Dicerna Pharmaceuticals, Inc.

在研适应症

代谢功能障碍相关的脂肪肝病

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

项与 SCAP 相关的临床试验

NCT06007651

/ Terminated临床1期

A Phase 1, Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial of LY3885125 to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Ascending Dose in Participants with Dyslipidemia and Repeat-Doses in Participants with NAFLD

The main purpose of this study is to evaluate the safety and tolerability of LY3885125 after administration of single ascending doses in participants with dyslipidemia (part A) and multiple doses in participants with non-alcoholic fatty liver disease (part B). Blood tests will be performed to check how much LY3885125 gets into the bloodstream and how long it takes the body to eliminate it.
The study will last up to approximately 49 weeks for part A and 62 weeks for part B, for a total of approximately 111 weeks.

开始日期2023-08-10

申办/合作机构

Eli Lilly & Co.

100 项与 SCAP 相关的临床结果

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100 项与 SCAP 相关的转化医学

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0 项与 SCAP 相关的专利（医药）

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825

项与 SCAP 相关的文献（医药）

2025-04-18·Science Advances

Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth

Article

作者: Mo, Xiaokui ; Fan, Yunzhou ; Su, Huali ; Guo, Deliang ; Liu, Yanwei ; Chiang, Cheng-Yao ; Magaki, Shino ; Yin, Xinmin ; Wang, Qiang ; Yong, William H ; Zhong, Yaogang ; Kou, Yongjun ; Zhang, Xiang ; Cloughesy, Timothy F. ; He, Liqing ; Geng, Feng ; Chakravarti, Arnab ; Lefai, Etienne

Elevated hexosamine biosynthesis fuels tumor growth by facilitating protein and lipid glycosylation. But which enzyme in this pathway is better to serve as an antitumor target remains unclear. Here, we revealed that targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, exhibits limited inhibitory effects on glioblastoma (GBM), the most lethal brain tumor. This outcome is due to the compensation of NAGK-mediated hexosamine salvage pathway. Unexpectedly, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, down-regulates the expression of other enzymes in this pathway and suppresses SREBP-1, a critical lipogenic transcription factor, effectively inhibiting GBM growth. Unexpectedly, SREBP-1 transcriptionally up-regulates the expression of hexosamine synthesis enzymes, while inhibition of these enzymes in turn down-regulates SREBP-1 activation via reducing N-glycosylation of its transporter, SCAP. Our study identified PGM3 as a promising target for treating GBM. Its inhibition disrupts the SREBP-1 activation-hexosamine synthesis positive feedback regulation to effectively eliminate GBM cells.

2025-04-01·International Journal of Biological Macromolecules

Genome-wide CRISPR screen reveals host factors for gama- and delta-coronavirus infection in Huh7 cells

Article

作者: Wang, Hongning ; Song, Cailiang ; Zhang, Tiejun ; Li, Yuqing ; Li, Hao ; Yang, Xin

Genome-wide CRISPR screening has emerged as a powerful tool for identifying novel host factors involved in viral infections. In recent years, host factors for several Alpha- and Beta-coronaviruses have been systematically screened and characterized. However, knowledge regarding Gamma- and Delta-coronavirus infections remains limited. In this study, we conducted genome-scale CRISPR knockout (KO) screening in Huh7 cells infected with infectious bronchitis virus (IBV), a Gamma-coronavirus, and porcine deltacoronavirus (PDCoV), a Delta-coronavirus. We identified known host factors for PDCoV, including APN and TMEM41B. We confirmed that human APN does not serve as a critical host factor for IBV. Notably, SPPL3 was identified as a key factor involved in viral particle entry and S protein-induced syncytium formation through the modulation of cellular N-glycosylation. Furthermore, we performed a meta-analysis integrating all Huh7 cell-based genome-wide CRISPR screens across the four genera of coronaviruses (Alpha-, Beta-, Gamma-, and Delta-coronaviruses). Our analysis highlighted conserved host pathways, particularly those related to proteoglycans, glycoproteins, and vesicle trafficking. TMEM41B, SCAP, and FAM98A emerged as the most frequently targeted host genes. These findings provide valuable insights into the life cycles of IBV and PDCoV infections and facilitate the development of host-directed therapeutic strategies.

2025-04-01·Poultry Science

Genome-wide association analysis identified the involvement of MRPS22 in the regulation of Muscovy duck broodiness

Article

作者: Yu, Shiqi ; Zhang, Cheng ; Wang, Xiao ; Yang, Wanli ; Chen, Xingyong ; Lin, Weihuang ; Yang, Xiaowei ; Guo, Liping ; Yu, Hailiang

Compared to Chinese domesticated duck, Muscovy duck is the only species that retains the broodiness characteristic. Strong broodiness seriously limits its reproductive performance. In order to explore the molecular mechanisms that regulate broody behavior in Muscovy duck, this study used whole genome resequencing (WGRS) to obtain genomic variation sites of Muscovy ducks and conducted association analysis with broody traits. A total of 6,131,623 Single Nucleotide Polymorphisms (SNPs)were obtained from 295 female Muscovy ducks. After genome wide association study (GWAS) with the total broody days, average broody days, broody frequency and the first day of broodiness, 39, 130, 29 and 138 significant SNPs were obtained, respectively. The key genes annotated to these SNPs loci include NCOA6, MRPS22, SCAP, CRY2, CK1δ and EZH1, which could be candidate genes regulating the broodiness of Muscovy ducks. Functional analysis showed that over expression of MRPS22 upregulated the expression of CYP19A1 to promote the synthesis of intracellular estradiol, and downregulated the expression of CYP11A1 and 3β-HSD to inhibit the synthesis of progesterone to regulate broodiness of Muscovy ducks. The genetic polymorphism results showed that MRPS22: g.19000662G>A was significantly associated with average broody days. The average broody days in GA mutant ducks increased by an average of 2.23 days compared to wild GG type, which can be used for molecular marker for broody behavior selection. In conclusion, our study revealed MRPS22 regulated the broody performance by affecting the synthesis of estradiol and progesterone, and g.19000662G>A in MRPS22 was significantly associated with average broody days of Muscovy duck.

项与 SCAP 相关的新闻（医药）

2025-04-26

·生物谷

Sci Adv：科学家识别出有望攻克人类最致命脑瘤的关键酶类靶点

本文研究不仅找到了一个新的治疗靶点—PGM3，还揭示了胶质母细胞瘤中糖胺聚糖合成途径与SREBP-1激活之间的复杂调控关系在癌症治疗的漫长征途中，胶质母细胞瘤（GBM，glioblastoma，）一直是难以攻克的堡垒，这种起源于脑内胶质细胞的恶性肿瘤生长迅速且侵袭性强，患者从确诊到死亡的中位生存期仅为12-16个月，即便经过手术、放疗、化疗等综合治疗也难以扭转其高致死率的局面。每年，全球约有15,000人被诊断出患有这种致命的脑肿瘤。近日，一篇发表在国际杂志Science Advances上题为“Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth”的研究报告中，来自美国俄亥俄州立大学综合癌症中心等机构的科学家们通过研究共同发现了一种名为PGM3的酶，通过靶向作用该酶有望有效抑制脑胶质瘤的生长，甚至消灭肿瘤细胞。肿瘤的快速生长离不开蛋白质和脂质的糖基化过程，简单来说，糖基化就是糖分子与蛋白质或脂质结合，这一过程为肿瘤细胞的增殖和扩散提供了必要的物质基础，而PGM3正是参与糖胺聚糖合成途径的关键酶，该途径产生的UDP-GlcNAc是蛋白质和脂质糖基化的重要底物。在这项研究中，研究人员发现，尽管在胶质母细胞瘤中作为糖胺聚糖合成限速酶的GFAT1表达显著上调，但靶向抑制GFAT1的效果却不尽如人意；原因在于，肿瘤细胞能通过NAGK介导的糖胺聚糖补救途径来补偿GFAT1抑制带来的影响，从而继续维持其生长所需的糖胺聚糖供应。然而当研究人员将目光转向PGM3时，他们却意外发现，抑制PGM3不仅能下调糖胺聚糖合成途径中其它酶的表达，还能有效抑制SREBP-1的激活，SREBP-1是一种关键的脂肪生成转录因子，其激活对于肿瘤细胞的脂质合成至关重要。进一步研究后，研究人员又揭示了一条正反馈调节环路，即SREBP-1能转录上调糖胺聚糖合成酶的表达，而这些酶的活性又会通过促进其转运蛋白SCAP的N-糖基化来稳定SREBP-1的激活，从而同时增加糖胺聚糖和脂质的合成，并能为肿瘤生长提供“燃料”，因此，靶向作用PGM3或能打破这一正反馈环路从而有效抑制胶质母细胞瘤的生长。本文研究不仅找到了一个新的治疗靶点—PGM3，还揭示了胶质母细胞瘤中糖胺聚糖合成途径与SREBP-1激活之间的复杂调控关系，此前研究多聚焦于GFAT1这一限速酶，但本文研究通过深入探究后发现，PGM3在调控糖胺聚糖合成途径中发挥着更为关键的作用；更重要的是，靶向作用PGM3能同时影响糖胺聚糖合成和脂质合成两条途径，并能从多个层面抑制肿瘤的生长，这就为开发更有效的胶质母细胞瘤治疗策略提供了全新的思路。 GBM能通过NAGK介导的己糖胺挽救途径来抵抗GFAT1的抑制作用此外，研究人员还通过临床样本分析并证实了PGM3在胶质母细胞瘤组织中的高表达，并在动物模型中验证了靶向作用PGM3抑制肿瘤生长的效果，这些发现不仅在基础研究层面具有重要意义，更为未来的临床应用奠定了坚实的基础。近年来，随着对癌症代谢重编程的深入理解，靶向代谢途径已成为癌症治疗的一个前沿热点领域，肿瘤细胞通过改变自身的代谢方式就能满足其快速生长和增殖的需求；其中，糖胺聚糖合成途径因其在肿瘤细胞中的异常激活而备受关注。然而尽管在多种癌症中都发现了这一途径的上调，但如何精准地靶向该途径以实现有效的肿瘤抑制，一直是困扰科学家的难题。胶质母细胞瘤作为最致命的原发性脑肿瘤，其治疗更是面临巨大挑战，传统的治疗方法效果有限且患者的预后极差。因此寻找新的分子靶点并开发更有效的治疗策略已经成为胶质母细胞瘤研究领域的迫切需求，而这项关于PGM3的研究无疑为攻克这一难题带来了新的希望。随着科学家们对PGM3功能的进一步研究及基于PGM3的药物研发的推进，未来他们有望开发出更精准、更有效的胶质母细胞瘤治疗方案，这不仅有望改善患者的预后，也为其它依赖糖胺聚糖合成途径的癌症患者的治疗提供了一定的借鉴。（生物谷Bioon.com）参考文献： HUALI SU,YAOGANG ZHONG,LIQING HE, et al. Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth, Science Advances (2025). DOI:10.1126/sciadv.adq0334.

临床2期

2025-02-10

·FierceBiotech

Eli Lilly inks duo of deals, teaming with AdvanCell, OliX to push deeper into radiopharma, MASH

Lilly gained a connection to AdvanCell when it bought Point Biopharma. \n Eli Lilly has begun the week with a bang. Early Monday morning, AdvanCell and OliX Pharmaceuticals put out news that the Big Pharma is coughing up cash to work with them on radiopharmaceuticals and metabolic-associated steatohepatitis (MASH), respectively.The deal with OliX gives Lilly global rights to OLX75016, a siRNA candidate that targets the expression of the MARC1 enzyme. OliX selected the target after looking at genomic variants linked to MASH and other liver diseases. The Korean biotech is running a phase 1 trial of the candidate in healthy volunteers, and Lilly will pay for OliX to complete the study.Striking the global licensing agreement moves Lilly deeper into siRNA and MASH. The drugmaker showed its interest in siRNA and related modalities last year by opening a $700 million nucleic acid R&D center in the Boston Seaport.Tirzepatide, the GLP-1 drug in Mounjaro and Zepbound, is Lilly’s highest-profile MASH candidate. Lilly reported phase 2 MASH data in June and later outlined its attempts to find biomarkers that can support accelerated FDA approvals in the liver disease. The company’s early-phase pipeline, which includes siRNA inhibitors of SCAP and PNPLA3, could benefit from the investments. Lilly gained a connection to AdvanCell, an Australian radiopharmaceutical company when it bought Point Biopharma for $1.4 billion in 2023. Point partnered with AdvanCell earlier that year, securing a chance to collaborate on the development of lead-212-labeled radioligands. The new deal builds on the existing pact to support the development of an expanded portfolio of lead-212 targeted alpha therapies.AdvanCell’s star has risen since it began working with Point in 2023. Last week, the biotech disclosed a $112 million series C that was co-led by SV Health Investors, Sanofi Ventures, Abingworth and SymBiosis. AdvanCell’s pipeline is led by a would-be challenger to Novartis’ prostate cancer drug Pluvicto.

临床1期引进/卖出并购临床2期临床结果

2022-07-05

·生物谷

Cell揭秘：阿尔兹海默病遗传最重要的风险因素

阿尔茨海默病（AD）是一种起病隐匿的进行性发展的神经系统退行性疾病。临床上以记忆障碍、失语、失用、失认、视空间技能损害、执行功能障碍以及人格和行为改变等全面性痴呆表现为特征，病因迄今未明。65岁以前发病者，称早老性痴呆；65岁以后发病者称老年性痴呆。AD其特征是广泛的神经变性，胶质增生和淀粉样-β（Aβ）斑块和tau蛋白神经纤维缠结。从研究来看，该病的可能因素和假说众多，反映了复杂的遗传和环境病因。绝大部分的流行病学研究提示，家族史是该病的危险因素。最近通过基因定位研究，发现脑内淀粉样蛋白的病理基因位于第21对染色体。与AD有关的遗传学位点，已知的至少有以下4个：早发型AD基因座分别位于2l、14、1号染色体。相应的可能致病基因为APP、S182和STM-2基因。迟发型AD基因座位于19号染色体，可能致病基因为载脂蛋白E（APOE）基因。载脂蛋白E ε4（APOE4）是AD最强的遗传危险因素，除非洲人的APOE4相关AD风险较低外，APOE4使欧洲人和东亚人的AD风险分别增加15倍及15倍以上。但是作为AD最强的危险因素，APOE4如何影响人脑细胞功能以及机制尚不清楚。近日，来自美国纽约西奈山伊坎医学院遗传学和基因组科学系的研究团队在Cell 杂志在线发表了题为“Cholesterol and matrisome pathways dysregulated in astrocytes and microglia”的研究，该研究揭示了APOE4驱动星形胶质细胞和小胶质细胞脂代谢失调，从而使得APOE4引发神经胶质细胞特异性细胞和非细胞自主失调，从而导致AD风险增加。这项研究从代谢的角度揭示了APOE4的作用机制，为理解AD发病提供新的视角。研究者们首先评估APOE4对人类脑细胞类型的影响，分析了APOE4对人群和同基因人类诱导多能干细胞(HiPSCs)、死后的脑组织和APOE靶向替换(APOE-TR)小鼠脑细胞类型的影响。人群和等位基因模型表明，APOE4局部单倍型，而不是单一的风险等位基因，是导致风险的因素。作者分析了13个人群hiPSC系（6个APOE 44和7个APOE 33），确认APOE4是AD遗传风险评分（GRS）的主要影响因素。通过1000G单倍型频率，作者定义了常见（hap.01-23）和稀有（hap.other）单倍型，识别了8个常见单倍型和 11个稀有单倍型。APOE4发生在7个独特的单倍型上，而APOE3发生在12个不同的单倍型上。通过RNA测序获得的转录本主成分分析(PCA)和Spearman相关性显示，样本按细胞类型聚集，而不是按APOE基因型区分。在iPSC重编程后，hiPSC分化为四种细胞类型：小胶质细胞、星形胶质细胞、混合皮质培养物、BMECs。接着，作者对每种细胞类型进行了差异表达基因(DEG)分析，发现星形胶质细胞中的DEGs > 小胶质细胞 > 混合皮质培养物，表明小胶质细胞和星形胶质细胞是受固有APOE基因影响的主要细胞类型。随后基因集富集分析显示小胶质细胞和星形胶质细胞中最显著的上调基因集是胆固醇生物合成和其他脂质途径。在小胶质细胞中，下调基因集包括高密度脂蛋白(HDLI)介导的脂质运输、通用转录途径和溶酶体。因此， APOE4与较高的胆固醇合成和较低的分解代谢/外排相关，APOE4小胶质细胞和星形胶质细胞中胞内胆固醇水平发生改变。随后，作者发现APOE4 AD星形胶质细胞显示出与APOE4 hiPSC混合皮质培养物相同的基质组相关模块，例如上调的趋化性、炎症和脂质合成。在APOE4 hiPSC混合皮质培养物和AD脑中均发现了由星形胶质细胞驱动的基质组，其与神经胶质细胞迁移、炎症和脂质合成有关。所有脑区的ECM、趋化因子和细胞因子信号通路在APOE4小胶质细胞中均呈阳性富集。更为有趣的是，研究者通过转录组学对APOE4、APOE3、Apoe KO和Apoe野生型(WT)的小鼠新生小胶质细胞和星形胶质细胞进行分析，发现APOE基因座附近的调控机制或结构在物种之间存在差异。小鼠Apoe和人APOE两者在功能上不一样，脂质代谢失调是人特异性的。其中，与APOE3相比，APOE4星形胶质细胞中胞内游离胆固醇显著增加。因果网络分析显示，SREBF2、SCAP和HMGCR在APOE4星形胶质细胞和小胶质细胞中激活，表明APOE4星形胶质细胞中的胞内胆固醇升高，胆固醇的从头合成也增加。同时，APOE4和脂质转运蛋白的减少导致胆固醇流出减少。这些数据表明，APOE4 星形胶质细胞和小胶质细胞中的胆固醇运转受损，LXR激动剂可逆转解偶的脂质代谢，但对不同细胞类型反应不同。进一步研究发现，肌动蛋白细胞骨架的调节是转录组学中最显著和负富集的基因组之一， APOE4星形胶质细胞的肌动蛋白细胞骨架失调与外部脂质暴露无关，但混合皮质培养物的去卷积星形胶质细胞与纯星形胶质细胞高度相关（95%–97%）。表明星形胶质细胞-神经元通讯驱动星形胶质细胞基质体信号，基质体则加剧APOE4星形胶质细胞的脂质失调。这项研究中，作者在hiPSC模型，AD患者的脑组织和APOE-TR小鼠证明了APOE4基因在人类当中的独特作用，揭示了APOE4共同驱动星形胶质细胞中的溶酶体胆固醇螯合，减少了胞质内游离的胆固醇，从而通过增加胆固醇生物合成和减少外排导致脂质失调。促炎基质组失调至少部分是由APOE4星形胶质细胞-神经元通讯引起的，并恶化脂质失调，包括胆固醇生物合成和外排。提示在APOE4携带者中，恢复神经胶质脂质稳态和炎症的治疗方法可能对AD患者有益。从全新的角度解释了APOE4在AD中的作用机制，为治疗提供新的策略。参考文献：Cell. 2022 Jun 23;185(13):2213-2233.e25.doi: 10.1016/j.cell.2022.05.017.Cholesterol and matrisome pathways dysregulated in astrocytes and microglia撰文 | Ann编辑 | 小耳朵上万科研人员交流基地，扫码加入“科研交流群”，找到组织，让科研更轻松！