更新于：2024-11-01

LeuRS

更新于：2024-11-01

基本信息

别名

亮氨酸tRNA连接酶、FLJ10595、FLJ21788

+ [11]

简介

Catalyzes the specific attachment of an amino acid to its cognate tRNA in a two step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. Exhibits a post-transfer editing activity to hydrolyze mischarged tRNAs.

关联

项与 LeuRS 相关的药物

GSK-3036656

靶点

LeuRS

作用机制

LeuRS抑制剂

在研机构

GSK Plc

原研机构

GSK Plc

在研适应症

肺结核 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Epetraborole

靶点

LeuRS

作用机制

LeuRS抑制剂

在研机构

AN2 Therapeutics, Inc. [+2]

原研机构

Anacor Pharmaceuticals LLC

在研适应症

非结核分枝杆菌感染 [+2]

非在研适应症

急性肾盂肾炎 [+6]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

ZCL-039

靶点

LeuRS

作用机制

LeuRS抑制剂

在研机构

Shanghai Institutes for Biological Sciences CAS

原研机构

Shanghai Institutes for Biological Sciences CAS

在研适应症

细菌性肺炎

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

项与 LeuRS 相关的临床试验

NCT06354257 / Recruiting临床1期

A Phase 1, Open-label, Fixed Sequence, 1-way Drug-drug Interaction Study to Investigate the Pharmacokinetics of GSK3036656 and an Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel When the Oral Contraceptive is Administered Alone and in Combination With GSK3036656 in Healthy Female Participants of Nonchildbearing Potential Aged 18-65 Years of Age

The purpose of this study is to provide data showing if there are any effects of GSK3036656 on a combined oral contraceptive containing Ethinyl Estradiol (EE) and Levonorgestrel (LNG), which will help inform future studies on suitable contraceptive measures to be used.

开始日期2024-04-05

申办/合作机构

GSK Plc

CTIS2023-507839-38-00 / Not yet recruiting

- 220104

开始日期2024-04-05

申办/合作机构

GlaxoSmithKline Research & Development Ltd.

NCT06114628 / Recruiting临床2期IIT

A Seamless Phase 2B/C Platform Trial to Evaluate Multiple Regimens and Durations of Treatment in Pulmonary Tuberculosis

The UNITE4TB consortium is a group of universities and pharmaceutical companies funded by the European Union. This consortium are carrying out a trial to find better and faster ways to treat tuberculosis (TB). The standard treatment for TB takes 24 weeks and uses four drugs. The consortium want to find new treatments that are faster but just as safe and effective.
In the trial, two new drugs will be used, BTZ-043 and GSK3036656, along with the drugs that are already used to treat TB in a variety of combinations (11 different combinations initially). These new drugs have worked well in tests with animals and have reduced the amount of TB bacteria in people's sputum/phlegm when used alone for two weeks. These new drugs will be used in combination with other TB drugs for a longer time (up to 16 weeks) in people with TB. The UNITE4TB consortium want to see if they work well and are safe.
This trial will take place at sites across the world and will involve people with TB of the lungs that would usually respond well to the standard treatment. But the new treatments being tested might also work for people with drug resistant TB, that's harder to treat.
The trial has two parts. In the first part, different combinations of drugs will be tried on up to 700 people for 16 weeks. These combinations will be compared to the standard 24-week treatment to see which ones work the best and are safe.
In the second part, the best combinations from the first part will be taken to try to find out what the best length of time is to give the treatment for. These combinations will be tried on up to 1800 people giving them either 8, 10, 12, 14 or 16 weeks treatment. The investigators will follow these people for a total of 72 weeks to make sure the treatment is working.
The UNITE4TB consortium hope that this trial will find new treatments that are fast, safe, and effective for both regular TB and resistant TB. If it works, it can then be tested again in a bigger trial to be sure.

开始日期2024-01-09

申办/合作机构

University College London

[+21]

100 项与 LeuRS 相关的临床结果

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100 项与 LeuRS 相关的转化医学

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0 项与 LeuRS 相关的专利（医药）

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704

项与 LeuRS 相关的文献（医药）

2024-11-01·Veterinary Medicine and Science

Potential Piperolactam A Isolated From Piper betle as Natural Inhibitors of Brucella Species Aminoacyl‐tRNA Synthetase for Livestock Infections: In Silico Approach

Article

作者: Dudi, Dudi ; Ramdani, Yoga ; Tumilaar, Sefren Geiner ; Kurnia, Dikdik ; Latipudin, Diding

ABSTRACTBrucellosis is an important global zoonosis caused by the bacterium Brucella sp. Brucellosis causes abortions, reproductive failure and reduced milk production, resulting in significant economic losses. Brucella species are reported to be resistant to antibiotics, which makes treatment difficult. The urgency of discovering new drug candidates to combat Brucella’s infection necessitates the exploration of novel alternative agents with unique protein targets. Aminoacyl‐tRNA synthetases (aaRSs), which have fundamental functions in translation, inhibit this process, stop protein synthesis and ultimately inhibit bacterial growth. The purpose of this study was to isolate piperolactam A compounds from the methanol extract of Piper betle leaves that have potential as antibacterials to inhibit the growth of Brucella sp. causing brucellosis in livestock and to analyse the mechanism of inhibitory activity of piperolactam A compounds against the aaRS enzyme through a molecular docking approach in silico. Piperolactam A was isolated from P. betle by column chromatography and characterized by UV, IR, 1D and 2D NMRs and MS, then tested for their inhibition mechanism against the enzymes threonyl‐tRNA synthetase, leucyl‐tRNA synthetase (LeuRS) and methionyl‐tRNA synthetase in silico. The result in silico test is that piperolactam A has the potential to inhibit LeuRS enzyme with the greater binding affinity.

2024-11-01·American Journal of Medical Genetics Part A

Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

Article

作者: Tsuyusaki, Yu ; Aida, Noriko ; Seki, Eijun ; Uehara, Takeshi ; Kumaki, Tatsuro ; Nonoda, Yutaka ; Kurosawa, Kenji ; Enomoto, Yumi ; Ishikura, Kenji

AbstractAcute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl‐tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17‐month‐old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high‐intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1‐related disorder.

2024-10-01·Plant Disease

First Report of Klebsiella variicola Causing Tomato Pith Necrosis in Yunnan Province, China

Article

作者: Li, Hong ; Li, Jing ; Shi, Qiaoli ; Yue, Suju ; Zhang, Shaolong ; Mo, Qiaoping ; Qi, Xiaoyu ; Li, Qin ; Wang, Guoping

Tomato (Solanum lycopersicum L.) is a key vegetable crop in China. In August 2023, an outbreak of bacterial pith necrosis in tomato occurred in Lufeng County, Yunnan Province, China, affecting over 40% of the tomato plants in a greenhouse. The stems of infected plants developed a waterlogged soft rot and the disease progressed, the lower leaves and lateral branches of infected plants gradually wilted and died. A longitudinal cut of the stem revealed hollow pith with brown vascular tissue. To isolate the pathogen, the plant surface was disinfested with 75% ethanol. Then, a piece of infected tissue from the base of the stem was excised and immersed in sterile water for 2 min. A small amount of liquid was streaked onto TTC (2,3,5-triphenyltetrazolium chloride) agar medium using an inoculation loop, and plates were incubated at 28℃ for 24 h. Colonies on the TTC plate were white, indicating that the pathogen was not Ralstonia solanacearum. Colonies grown on LB (Luria-Bertani) agar medium were randomly selected and subjected to preliminary pathogenicity tests. Based on the results, a colony named Kv4 was selected and purified through six subcultures in LB agar medium. Biochemical tests showed the strain utilized D-sorbitol, raffinose and citrate but not adonitol, and was positive for methyl red, D-glucose (acid), urea hydrolysis, lysine decarboxylase, and motility, and negative for phenylalanine deaminase, H2S production, indole production, and ornithine decarboxylase. These characteristics align with Klebsiella species (Garrity et al. 2007). To determine the species of strain Kv4, partial sequences of the 16S rDNA, phoE, leuS, and rpoB genes were amplified (Barrios-Camacho et al. 2019) and sequenced. Through BLASTn analysis, strain Kv4 sequences of 16S rDNA (OR888750) had 99.47% identity (1488/1496 bp), phoE (OR899599) had 98.69% (605/613 bp) identity, leuS (OR899598) had 99.07% identity (959/968 bp), and rpoB (OR899597) had 97.69% (633/648 bp) identity with Klebsiella variicola strain FF0907. Using the ClustalW algorithm in MEGA11 for nucleotide sequence alignment, phylogenetic trees were constructed with 16S and phoE, leuS, and rpoB via the neighbor-joining method, confirming strain Kv4 as K. variicola. To test pathogenicity, the roots of 25 'Moneymaker' tomato plants with four to five true leaves were wounded, then each plant inoculated with a 15 mL bacterial suspension (OD600=0.6) of strain Kv4, while the control plants received sterile water. Plants were incubated at 28℃ with a 16 h photoperiod. Experiments were done twice. At 15 days after inoculation (DAI), all plants inoculated with Kv4 showed yellowing, unevenly distributed small black necrotic spots on the leaf surface, and purple-brown soft rot at the stem base. By 18 DAI, there was a gradual transformation of the stem bases from green to purplish brown. At 21 DAI, 60% of the inoculated plants displayed brownish soft rot at the stem base. In contrast, the control plants remained symptom-free. The pathogen was re-isolated from the stem and identified as K. variicola via sequence analysis of 16S, phoE, leuS, and rpoB. In recent years, several new bacterial pith necrosis diseases were reported in tomato (Guo et al. 2023; Ivić et al. 2023). This is the first study documenting K. variicola causing bacterial pith necrosis in tomato. Once considered a benign plant endophyte, Sun et al. (2023) reported K. variicola causing banana sheath rot in Guangdong and Guangxi Provinces, China. Malik et al. (2023) reported that K. variicola caused leaf streak in sorghum in India. This report of bacterial pith necrosis in tomato caused by K. variicola strain Kv4 underscores the escalating threat posed by emerging pathogens to agricultural production. The emergence of K. variicola as a tomato pathogen complicates plant disease management strategies.

项与 LeuRS 相关的新闻（医药）

2024-10-12

·凯莱英药闻

本周国内创新药IND和NDA、上市获批，全球新药III期临床汇总

欢迎关注凯莱英药闻（收集周期：10.7-10.12，国内部分为首次申请临床、首次申请上市、首次获批上市的创新药）国内创新药IND汇总 1、诺华：VHB937注射用浓溶液作用机制：TREM2单抗适应症：神经退行性疾病 10月9日，诺华的VHB937注射用浓溶液的临床试验（IND）申请获CDE受理。VHB937是一款抗TREM2单抗；TREM2是一种与多种配体相互作用的受体，其编码变异会增加阿尔茨海默症和其他神经退行性疾病的风险；此外，由于TREM2也由肿瘤浸润的巨噬细胞表达，与抗PD-1联合应用时，抗TREM2单抗抑制肿瘤生长并促进肿瘤消退。 2、阿斯利康：AZD6234注射液作用机制：胰淀素类似物适应症：肥胖 10月11日，阿斯利康的AZD6234注射液的IND申请获CDE受理。AZD6234 是一款长效胰淀素受体激动剂和 CALCR 受体激动剂，目前正开发用于治疗肥胖。阿斯利康曾表示，未来的市场将不再以治疗肥胖为中心，而是转向长期、持续的体重管理。 3、盟科药业：MRX-5片作用机制：LeuRS抑制剂适应症：细菌感染 10月12日，盟科药业的MRX-5片的IND申请获CDE受理。MRX-5是一种新型苯并硼唑类抗生素，用于治疗分枝杆菌属，特别是由非结核分枝杆菌（NTM）引起的感染。非结核分支杆菌是指除了结核分枝杆菌复合群和麻风分枝杆菌之外的一大类分枝杆菌，最常见的致病性NTM包括鸟分枝杆菌复合群和脓肿分枝杆菌等。目前，NTM病的发病率和患病率持续增长，且药物治疗的疗程长、不良反应多、疗效和预后欠佳，可能导致高发病率与高死亡率相关的衰弱性肺部疾病。临床前研究显示，MRX-5对于大多数常见的NTM菌都有着良好的抗菌活性和安全性，有望为NTM病的治疗提供一种潜在的新选择。 4、恒瑞医药：注射用SHR-9839(皮下) 作用机制：靶向EGFR/c-Met双特异性抗体适应症：实体瘤 10月12日，恒瑞医药的注射用SHR-9839(皮下) 的IND申请获CDE受理。SHR-9839是恒瑞开发的一款靶向EGFR和c-MET的双特异性抗体，并进行c-MET双表位、Fc去岩藻糖化修饰等改造，有望通过信号通路双重阻断和ADCC增强等机制进一步发挥抗肿瘤作用。临床前药效研究发现，SHR-9839对EGFR和/或MET突变或异常的人肿瘤裸小鼠移植瘤模型有明显疗效。国内创新药NDA汇总 1、礼来：米吉珠单抗注射液作用机制：抗IL-23p19单抗适应症：克罗恩病 10月9日，礼来的米吉珠单抗注射液以及其皮下注射剂型的上市申请获CDE受理。米吉珠单抗（mirikizumab）是一种白细胞介素 23（IL-23）p19 拮抗剂，可与IL-23的p19亚基结合，进而阻断IL-23介导的炎症反应。2023年10月，FDA批准mirikizumab（商品名：Omvoh）的上市申请，用于治疗成人中度至重度活动性溃疡性结肠炎 (UC)，是礼来首个获批治疗UC的药物。据推测，本次在国内申报适应症可能为克罗恩病（CD），该适应症此前已在国内被纳入突破性疗法认定。2023年10月，礼来公布了其用于治疗患有中度至重度活动性CD的成人的VIVID-1研究，显示mirikizumab达到了共同主要终点和所有主要次要终点，即：（1）与安慰剂组相比，mirikizumab组在第12周获得临床应答和第52周获得临床缓解的患者比例更高（45.4% vs 19.6%，P<0.000001）；（2）与安慰剂组相比，mirikizumab组在第12周获得临床应答和在第52周获得内镜应答的比例更高（38.0% vs 9.0%，p<0.000001）；（3）与安慰剂组相比，mirikizumab组在第52周达到了所有单个和复合主要次要终点（p<0.000001）；其中，有54.1%的患者在第52周达到临床缓解，而安慰剂组这一比例为19.6%（p<0.000001）；（4）在临床缓解的终点上，mirikizumab与乌司奴单抗相比表现出非劣效性；（5）在第52周的内镜应答终点上，mirikizumab没有达到优于乌司奴单抗的效果，尽管mirikizumab的结果在数值上更高，特别是在非多重性控制的生物疗法失败人群中。 2、恒瑞医药：SHR2554片作用机制：EZH2抑制剂适应症：淋巴瘤 10月11日，恒瑞医药的SHR2554片的上市申请获CDE受理。SHR2554是一款新型、高效、选择性的口服EZH2抑制剂，可以选择性抑制野生型和突变型EZH2酶活性。EZH2在多种肿瘤中均发现高表达，且与肿瘤预后存在相关性，包括胃癌、乳腺癌、头颈癌、血液系统恶性肿瘤等。2023年2月，恒瑞将SHR2554除大中华区以外的全球授权，有偿许可给Treeline Biosciences，有望获得高达7.06亿美元的付款。 2024年4月，公司披露了在复发或难治性外周T细胞淋巴瘤患者中的I期数据，显示在既往接受过2线以上的抗癌治疗的18名患者中，客观缓解率为61%，中位缓解持续时间为12.3个月。中位无进展生存期为11.1个月， 12个月总生存率为92%。最常见的3级或4级治疗相关不良事件是血小板计数减少、白细胞计数减少、中性粒细胞计数减少和贫血。没有报告与治疗相关的死亡事件发生。国内创新药上市获批 1、渤健：托夫生注射液作用机制：—— 适应症：肌萎缩侧索硬化 10月8日，NMPA批准渤健的托夫生注射液的上市申请，用于治疗超氧化物歧化酶1（SOD1）突变所致的肌萎缩侧索硬化（ALS）患者。托夫生（tofersen）是由Ionis开发的一种反义药物，渤健根据合作开发和许可协议从Ionis获得了tofersen的许可。该药物能够与编码SOD1 的 mRNA结合，被核糖核酸酶RNase-H降解，从而减少突变SOD1蛋白的生成。2023年4月，FDA加速批准tofersen的上市申请，成为首款针对ALS的基因靶向疗法。在全球的III期临床试验中，托夫生表现出了显著的疗效。接受托夫生治疗的参与者的 CSF SOD1 蛋白和神经丝（神经元损伤的标志物）浓度降低，在 VALOR III 期临床试验中，未达到 ALSFRS-R 减缓下降的主要结局指标，但在 VALOR 试验后的开放标签扩展中，与从安慰剂过渡到托夫生的参与者相比，开始使用托夫生的参与者显示ALSFRS-R 的下降有所减少。 2、君实生物：昂戈瑞西单抗注射液作用机制：PCSK9单抗适应症：血脂异常 10月11日，NMPA批准君实生物的昂戈瑞西单抗注射液的上市申请，与他汀类药物、或者与他汀类药物和依折麦布联合用药，用于原发性高胆固醇血症（非家族性）和混合型血脂异常的成人患者。昂戈瑞西单抗是一种靶向前蛋白转化酶枯草溶菌素9（PCSK9）的全人源单克隆IgG1抗体，通过特异性结合PCSK9，阻断PCSK9与低密度脂蛋白受体（LDLR）结合，阻止PCSK9介导的LDLR降解，提高细胞表面LDLR数目，进而降低血清中LDL-C水平。该药物的获批主要基于两项多中心、随机、双盲、安慰剂对照的Ⅲ期临床研究：（1）JS002-003研究结果显示，相较安慰剂，昂戈瑞西单抗150mg每2周一次（Q2W）或300mg每4周一次（Q4W）皮下注射，可显著降低LDL-C水平达60%以上，且在52周的治疗期间始终维持稳定的降幅，同时对其他血脂参数，如非高密度脂蛋白胆固醇（non-HDL-C）、载脂蛋白B（Apo B）和总胆固醇（TC）也有明显的改善作用；安全性良好，未发现新的安全信号。（2）JS002-006研究结果显示，无论昂戈瑞西单抗PFS还是AI给药，均表现出相当的显著降脂作用，与安慰剂相比，患者接受昂戈瑞西单抗150mg Q2W治疗12周时，LDL-C水平显著降低70%以上（PFS组72.7%，AI组71.1%），且安全性良好。全球新药III期临床汇总感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

临床申请临床3期申请上市抗体药物偶联物

2024-09-28

·今日头条

可抑制癌细胞生长！李积彬教授团队发文：发现癌症诊断和治疗的潜在靶点

【导读】线粒体-细胞核通讯在维持细胞稳态中起着至关重要的作用。MOTS-c是一种来源于线粒体DNA 12S rRNA的短肽，已被认为是一种逆行线粒体信号。虽然最近的临床研究表明MOTS-c与人类肿瘤之间可能存在联系，但MOTS-c在肿瘤发生中的作用仍有待研究。 9月25日，李积彬教授研究团队在期刊《Advanced Science》上发表了题为“Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination”的研究论文，本研究中，研究人员发现MOTS-c水平在卵巢癌患者的血清和肿瘤组织中均降低，与患者的不良预后相关。外源性MOTS-c抑制OC细胞的增殖、迁移和侵袭，并诱导细胞周期阻滞和凋亡。机制上，MOTS-c与LARS1相互作用并促进其泛素化和蛋白酶体降解。此外，USP7是LARS1的去泛素化酶，MOTS-c可通过与USP7竞争与LARS1结合来减弱USP7介导的LARS1去泛素化。另外，研究人员发现LARS1在卵巢癌中表达升高，并发挥重要的致癌功能。更重要的是，MOTS-c对OC具有明显的抗肿瘤作用，且无全身毒性。综上所述，本研究揭示了MOTS-c在卵巢癌中的重要作用，为MOTS-c作为卵巢癌治疗靶点提供了可能。 https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202405620 背景知识 01 卵巢癌(OC)是最致命的妇科恶性肿瘤，2020年全球新诊断31.4万例，同年死亡20.7万例。尽管OC患者通过手术和化疗获得了暂时的临床缓解，但可用的治疗方案仍然有限，尤其是那些面临肿瘤复发和化疗药物耐药的患者。因此，在过去的30年里，OC患者的总生存率没有显示出实质性的提高。仅30.8%的晚期OC患者能生存5年。因此，迫切需要寻找新的抗肿瘤靶点及其治疗药物来延长OC患者的生存期。线粒体是生物能和生物合成细胞器。癌细胞通过重编程线粒体代谢来维持其增殖，从而为脂质、核酸和蛋白质合成提供原料。此外，线粒体也是细胞内通讯和信号转导的重要枢纽。在代谢应激下，线粒体通过产生多种逆行信号改变核基因表达，帮助细胞适应受损的稳态。线粒体-细胞核通讯的参与在肿瘤细胞中经常观察到。因此，靶向这些线粒体逆行信号(线粒体ROS、肿瘤代谢物、线粒体钙等)是目前很有前景的抗癌策略。 MOTS-c是一种由线粒体12S rRNA编码的线粒体来源的16个氨基酸组成的多肽，近年来被认为是参与线粒体逆行信号调节的关键因子。在代谢应激时，MOTS-c转位至细胞核并与转录因子NRF2结合，参与调控核基因表达，维持细胞稳态。最近有报道称，MOTS-c在乙型肝炎病毒相关肝细胞癌患者中减少，外源性MOTS-c通过促进线粒体融合抑制乙型肝炎病毒DNA复制，从而保护肝功能。此外，肺癌患者放疗后MOTS-c水平显著升高。另外，MOTS-c与患前列腺癌和乳腺癌的可能性相关，且存在种族差异。所有这些研究均提示MOTS-c与肿瘤发生可能存在关联。然而，MOTS-c在包括OC在内的人类肿瘤中的生物学功能仍未被探索。 LARS1是OC的促癌因子 02 虽然LARS1在其他肿瘤中已被证明是一种促进癌症发展的分子，但在OC中的作用尚不明确。为了阐明LARS1在OC中的功能，研究人员构建了LARS1 shRNA质粒并降低了OC细胞中LARS1的表达。LARS1沉默显著降低了OC细胞的增殖能力，如CCK8和克隆形成试验所示。同时，LARS1水平的降低也导致OC细胞的迁移和侵袭能力明显低于阴性对照组。总之，这些发现表明LARS1是OC中的一种促进癌症发展的因子。然而，LARS1如何影响OC细胞的生长仍不清楚。LARS1作为已知的mTORC1激活剂，前期数据也证实MOTS-c可以降低OC细胞中LARS1蛋白水平并抑制mTORC1信号通路，这表明LARS1可能通过mTORC1信号通路影响OC细胞的生长。为了证实这一点，研究人员在OC细胞SKOV3中过表达LARS1，并用雷帕霉素（RAPA，一种mTORC1抑制剂）对其进行处理。结果显示，RAPA显著逆转了LARS1过表达引起的细胞增殖、迁移和侵袭能力增强。上述结果表明，LARS1通过调节mTORC1信号通路影响OC的肿瘤进展。过表达LARS1逆转MOTS-c介导的卵巢癌肿瘤抑制作用 03 为了进一步确定LARS1通过MOTS-c治疗而下调与OC细胞增殖、迁移和侵袭之间的关系，研究人员建立了A2780和SKOV3细胞的稳定过表达LARS1模型。CCK8和克隆形成实验表明，LARS1的过表达显著增强了A2780和SKOV3细胞的增殖，并减轻或部分逆转了MOTS-c治疗引起的增殖抑制。同样，伤口愈合和迁移实验的结果表明，LARS1水平的升高显著增强了OC细胞的迁移和侵袭能力，从而抵消了MOTS-c的作用。这些发现表明，MOTS-c通过靶向LARS1来抑制OC的进展。 MOTS-c在体内显示出显著的抗肿瘤作用，能够抑制OC的生长，同时没有明显的系统毒性 04 为了评价MOTS-c在体内的抗肿瘤效果，研究人员利用A2780细胞构建了雌性裸鼠异种移植模型。结果显示，MOTS-c治疗显著抑制了OC细胞的生长，减少了肿瘤体积和重量。免疫组化分析显示，MOTS-c治疗抑制了肿瘤细胞的增殖，Ki67阳性细胞比例显著低于对照组。同时，MOTS-c治疗后LARS1的表达显著降低。此外，为了评估MOTS-c在体内是否有毒性，研究人员对两组小鼠的心脏、肝脏和肾脏进行了H&E染色，并从两组小鼠中收集了血清样本进行生化检测。在组织病理切片和生化检测结果的分析中未发现明显的毒性。综上所述，上述结果表明MOTS-c在体内可抑制OC细胞的生长且无毒性。 MOTS-c在体内显示出显著的抗肿瘤作用，对OC生长无系统毒性研究小结 05 总之，研究人员已经证实MOTS-c在OC中的表达减少，并且低水平的MOTS-c表达与不良预后相关。体外和体内实验表明，外源性MOTS-c可以抑制OC细胞的生长。机制上，MOTS-c通过抑制USP7介导的LARS1去泛素化作用并促进LARS1降解来发挥抗癌作用。本研究首次揭示MOTS-c作为一种抗肿瘤肽可以抑制OC进展，因此它可能是未来OC诊断和治疗的一个潜在靶点。【参考资料】 https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202405620 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会点击对应文字查看详情

临床研究放射疗法

2024-08-09

·Pharmaceutical Technology

AN2 slashes staff by 50% after lead antibiotic flunks in Phase II/III trial

While the Phase II portion of the study evaluating AN2’s epetraborole met the primary endpoint, it failed in a “key” secondary endpoint prompting trial termination. Image Credit: kora_sun / Shutterstock. AN2 Therapeutics has implemented cost-saving measures after “disappointing” topline results from Phase II part of the Phase II/III trial evaluating its lead antibiotic, epetraborole. The antibiotic’s development suffered a major setback a few months ago after AN2 voluntarily stopped enrolment in the Phase III portion of the trial. The decision followed a blinded aggregate data analysis indicating “potentially lower than expected efficacy”. Following the news, AN2’s stock was down by over 22.7% in premarket trading today (9 August), compared to the market close on 8 August. The company’s stock has been floundering since it took a nosedive in February after AN2 announced plans to pause enrolment in the Phase III portion of the trial. AN2 plans to cut 50% of its workforce by the end of the year. The restructuring is expected to cost approximately $2m – $3m. Furthermore, AN2’s chief medical officer, Dr Paul Eckburg, will leave the company by 30 August as part of the restructuring. The cost savings measures are expected to provide AN2 a cash runway through 2027. With the announcement of job cuts, AN2 joins the likes of FibroGen , Aerovate Therapeutics and Allakos , all of which have reduced their headcounts after trial failures this year. See Also: Bavarian Nordic wins positive CHMP opinion to amend Imvanex approval EAN 2024: anti-CGRPs more effective than onabotulinumtoxinA in chronic migraine prevention in real world Epetraborole is a bacterial leucyl-tRNA synthetase inhibitor. AN2 licensed the therapy from Pfizer , who gained it as part of a $5.2bn acquisition of Anacor Pharmaceuticals . AN2 was evaluating epetraborole as a treatment for refractory mycobacterium avium complex (MAC) lung disease. The placebo-controlled Phase II/III trial (NCT05327803) enrolled 80 patients with treatment refractory MAC lung disease. Although the Phase II portion met its primary endpoint of patient-reported response, there was no significant difference between the treatment and placebo arms in a “key” secondary endpoint of sputum culture conversion at six months. Whilst AN2 has shut down the development of epetraborole in MAC lung disease, it plans to start a Phase II trial evaluating the therapy in melioidosis, a bacterial infection. Another therapy in AN2’s pipeline is AN2-502998 for the treatment of Chagas disease , an infectious illness caused by a parasite transmitted by ticks.