更新于：2024-04-01

KARS

赖氨酸-tRNA连接酶

更新于：2024-04-01

基本信息

别名

deafness, autosomal recessive 89、DFNB89、KARS

+ [8]

简介

Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 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 (PubMed:9278442, PubMed:18029264, PubMed:18272479). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (PubMed:15851690). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:5338216, PubMed:14975237, PubMed:19524539, PubMed:23159739). (Microbial infection) Interacts with HIV-1 virus GAG protein, facilitating the selective packaging of tRNA(3)(Lys), the primer for reverse transcription initiation.

关联

项与 KARS 相关的药物

ZMA-001

靶点

KARS

作用机制

KARS抑制剂

在研机构

Zymedi Co. Ltd.初创企业

原研机构

Zymedi Co. Ltd.初创企业

在研适应症

肺动脉高压

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

YH-Chem-4

靶点

KARS

作用机制

KARS抑制剂

在研机构-

原研机构

Yuhan Corp.

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 KARS 相关的临床试验

NCT05967299 / Recruiting临床1期IIT

A Phase 1 Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Intravenous ZMA001 in Healthy Subjects

Background:
A number of diseases can cause a type of lung injury called pulmonary arterial hypertension (PAH). Most people who develop PAH do not survive more than a few years. A new study drug (ZMA001) may help. ZMA001 is a monoclonal antibody. This type of drug consists of proteins, made in a facility, that are very similar to proteins in a human body. But before giving ZMA001 to people sick with PAH, researchers want to find out how the drug affects healthy people.
Objective:
To test a drug (ZMA001) in healthy volunteers.
Eligibility:
Healthy adults aged 18 to 60 years.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have a urine test for drug use. They will have a test of their heart function.
Participants will come to the clinic for 1 inpatient visit of up to 48 hours.
ZMA001 is a liquid administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive this drug only once, during their inpatient stay. Some participants will receive the drug; others will receive a placebo. A placebo is a treatment that looks just like the real drug but contains no medicine. Participants will not know which treatment they are getting.
After a screening visit, participants will have 1 inpatient visit and up to 6 outpatient visits over 16 weeks after receiving the treatment. Blood draws and other tests will be repeated. Each outpatient visit is approximately 2 hours long.
This study is the first time ZMA001 will be administered to people.

开始日期2023-11-27

申办/合作机构

Lung and Blood Institute

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100 项与 KARS 相关的临床结果

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100 项与 KARS 相关的转化医学

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0 项与 KARS 相关的专利（医药）

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801

项与 KARS 相关的文献（医药）

2024-02-24·Scientific reports

Behavioral analysis of kainate receptor KO mice and the role of GluK3 subunit in anxiety.

Article

作者: Izumi Iida ; Kohtarou Konno ; Rie Natsume ; Manabu Abe ; Masahiko Watanabe ; Kenji Sakimura ; Miho Terunuma

Kainate receptors (KARs) are one of the ionotropic glutamate receptors in the central nervous system (CNS) comprised of five subunits, GluK1-GluK5. There is a growing interest in the association between KARs and psychiatric disorders, and there have been several studies investigating the behavioral phenotypes of KAR deficient mice, however, the difference in the genetic background has been found to affect phenotype in multiple mouse models of human diseases. Here, we examined GluK1-5 single KO mice in a pure C57BL/6N background and identified that GluK3 KO mice specifically express anxiolytic-like behavior with an alteration in dopamine D2 receptor (D2R)-induced anxiety, and reduced D2R expression in the striatum. Biochemical studies in the mouse cortex confirmed that GluK3 subunits do not assemble with GluK4 and GluK5 subunits, that can be activated by lower concentration of agonists. Overall, we found that GluK3-containing KARs function to express anxiety, which may represent promising anti-anxiety medication targets.

2024-02-02·RNA (New York, N.Y.)

Fungi of the order Mucorales express a "sealing-only" tRNA ligase.

Article

作者: Khondakar Sayef Ahammed ; Ambro van Hoof

Some eukaryotic pre-tRNAs contain an intron that is removed by a dedicated set of enzymes. Intron-containing pre-tRNAs are cleaved by tRNA splicing endonuclease (TSEN), followed by ligation of the two exons and release of the intron. Fungi use a "heal and seal" pathway that requires three distinct catalytic domains of the tRNA ligase enzyme, Trl1. In contrast, humans use a "direct ligation" pathway carried out by RTCB, an enzyme completely unrelated to Trl1. Because of these mechanistic differences, Trl1 has been proposed as a promising drug target for fungal infections. To validate Trl1 as a broad-spectrum drug target, we show that fungi from three different phyla contain Trl1 orthologs with all three domains. This includes the major invasive human fungal pathogens, and these proteins can each functionally replace yeast Trl1. In contrast, species from the order Mucorales, including the pathogens Rhizopus arrhizus and Mucor circinelloides, have an atypical Trl1 that contains the sealing domain but lacks both healing domains. Although these species contain fewer tRNA introns than other pathogenic fungi, they still require splicing to decode three of the 61 sense codons. These sealing-only Trl1 orthologs can functionally complement defects in the corresponding domain of yeast Trl1 and use a conserved catalytic lysine residue. We conclude that Mucorales use a sealing-only enzyme together with unidentified non-orthologous healing enzymes for their heal and seal pathway. This implies that drugs that target the sealing activity are more likely to be broader-spectrum antifungals than drugs that target the healing domains.

2024-01-10·Journal of biomolecular structure & dynamics

QM/MM investigation of the discriminatory pre-transfer editing mechanism operated by Lysyl-tRNA synthetase.

Article

作者: Bogdan F Ion ; Mohamed M Aboelnga ; James W Gauld

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that remarkable facilitate the aminoacylation process during translation. With a high fidelity, the mischarged tRNA is prevented through implementing pre- and post-transfer proofreading mechanisms. For instance, Lysine-tRNA synthetase charges the native substrate, lysine, to its cognate tRNA. In spite of the great structural similarity between lysine to the noncognate and toxic ornithine, with the side chain of lysine being only one methylene group longer, LysRS is able to achieve this discrimination with a high efficiency. In this work, the hybrid quantum mechanics/molecular mechanics (QM/MM) investigation was applied to probe the pre-transfer editing mechanism catalyzed by lysyl-tRNA synthetase to reject the noncognte aminoacyl, L-ornityl (Orn), compared to the cognate substrate, L-lysyl. Particularly, the self-cyclization pre-transfer editing mechanism was explored for the two substrates. The substrate-assisted self-cyclization editing of Orn-AMP, where its phosphate moiety acts as the catalytic base, is found to be the rate-determining step with an energy barrier of 101.2 kJ mol^-1. Meanwhile, the corresponding rate-limiting pathway for the native Lys-AMP lies at 140.2 kJ mol^-1. This observation clearly indicated the infeasibility of this catalytic scenario in the presence of the native substrate. Interestingly, a thermodynamically favorable cyclic product of -92.9 kJ mol^-1 with respect to the aminoacyl reactant complex demonstrated evidence of a successful pre-transfer editing. This reaction resulted in the discharge of the on-cognate -ornithine derivative from LysU's active site. These valuable mechanistic insights are valuable to enrich our knowledge of this extremely efficient and specific catalytic machinery of LysRS.Communicated by Ramaswamy H. Sarma.

项与 KARS 相关的新闻（医药）

2024-02-08

·PRNewswire

First in Human Dosed in Clinical Trial of ZMA001 for Treatment of Pulmonary Arterial Hypertension (PAH)

INCHEON, South Korea, Feb. 7, 2024 /PRNewswire/ -- Zymedi announced today that the first in human dosage of ZMA001, a monoclonal antibody being developed as a first-in-class treatment for Pulmonary Arterial Hypertension (PAH) has been initiated. The placebo-controlled phase 1 trial designed to ascertain the safety and dosage of ZMA001 is a collaborative effort between Zymedi and the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH). In the preceding year, both organizations entered into a Cooperative Research & Development Agreement (CRADA) in order to work together to advance the development of ZMA001. PAH is a serious and life-threatening condition affecting approximately 3 persons per 100,000 globally, with about 500 to 1,000 new cases diagnosed annually in the U.S. It is characterized by the narrowing of pulmonary arteries, a rise in pulmonary vascular resistance, and eventually death due to right heart failure. Current treatments for PAH, such as vasodilators, reduce symptoms but do not treat the underlying cause of the problem. ZMA001 is a first-in-class therapeutic antibody targeting the novel pro-inflammatory factor KARS1 that is specific to monocytes and macrophages. It can improve both the survival rates and the quality of life of PAH patients by eliminating the root pathologic cause of PAH. "We are excited to initiate this first in human trial of ZMA001, which marks a significant milestone for our company and the fight against PAH," said Dr. Sunghoon Kim, CEO and Founder of Zymedi. "We are scheduled to assess the safety and tolerability of ZMA001 through dose escalation clinical trials, systematically observing adverse reactions as dosage increases. Furthermore, we aim to establish the recommended dosage and determine the Maximum Tolerated Dose (MTD) for forthcoming phase 1b/2a clinical trials involving patients." The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. About ZMA001 ZMA001 is a human monoclonal antibody designed to control or inhibit inflammation responses in pulmonary blood vessels by blocking lysyl-tRNA synthetase (KARS1)-dependent infiltration of monocytes and macrophages. ZMA001 specifically targets membrane-exposed KARS1 without affecting its catalytic activity for protein synthesis. It can assure specificity toward response, disease indication, immune system, and target biology without inducing the systemic hypotension frequently observed with other typical treatments using vasodilators. ZMA001 with its novel MOA, is expected to treat PAH by eliminating its root pathologic cause unlike other treatments such as vasodilators that only address the symptoms. About Zymedi Zymedi is a global biopharmaceutical company that is committed to transforming the role of ARSs (Aminoacyl-tRNA Synthetases) and targeting it as a method of discovering and developing innovative treatments for patients with serious and life-threatening conditions that have no standard of care or lack effective therapy. For more information, please visit SOURCE Zymedi

临床1期

2024-01-01

·药明康德

前沿 |《自然》重磅揭示多个KRAS小分子靶向位点！

▎药明康德内容团队编辑上世纪70年代，生物学家在研究鸡体内的Rous肉瘤病毒时发现了一种名为RAS的基因，它与肿瘤的发展密切相关。随后，其他研究者从Kirsten肉瘤病毒发现了另一种导致肿瘤生长的KRAS基因，其原本负责调控细胞生长、分化和存活，也属于RAS基因家族的一员。在长达数十年的研究历程中，科学家已经确认KARS突变是推动细胞走向癌变的关键因素，大约在十分之一的癌症类型中，都能见到KRAS突变的身影。尽管我们已经知道了作案对象，但几乎很难对KRAS下手，因为KRAS蛋白表面是名副其实的光滑，没有什么地方让药物嵌入，因此长久以来被认为难以成药，直到近年KRAS G12C共价抑制剂Lumakras（sotorasib）与Krazati（adagrasib）的获批才打破此一现象。相关阅读：征服不可成药靶点KRAS，这些新进展你知道吗？近期《自然》杂志的一项重磅研究可能会让KRAS靶向疗法的开发往前更进一步。来自西班牙巴塞罗那基因组调控中心与英国惠康桑格研究所的科学家合作，全面鉴定出了KRAS蛋白中的变构控制位点，并构建出了KRAS蛋白的完整变构控制图谱。以此为基础，研究找到了多个可以供化学药物分子结合的位点。变构是蛋白质调节其功能和活性的关键过程，当调节分子与蛋白质上的变构位点结合时，会促使蛋白形状变化。与直接抑制蛋白质活性位点相比，靶向变构位点更具特异性，并且能减少副作用，因为这种抑制作用只是微妙地改变了蛋白朝某一活性结构变化。2021年，美国FDA批准了sotorasib用于治疗携带KRAS G12C突变的非小细胞肺癌患者，这款新药就是一种变构抑制剂，能让KRAS处于无活性的结构状态。如果我们有更多的变构位点信息，那么将有更多潜在的药物被挖掘出来。为此，作者采用了一种多维深度突变扫描的方式，通过两轮突变构建了三个KRAS突变体文库，其中包含了超过2.65万个KRAS突变体，每个突变体一次只会改变1-2个氨基酸。所有的KRAS突变体都被用于测试与其他6种结合蛋白的相互作用，这些蛋白包括了结合后会促进癌症发生的类型，比如RAF1和PI3KCG蛋白。研究获得的大量数据都会用AI模型进行分析，主要用于确认哪些突变体会改变KRAS变构效应，哪些突变体又与6种蛋白有着更强的结合力。▲研究展示的KRAS（蓝色）与RAF1（黄色）相互作用（图片来源：Weng, Faure and Escobedo/Centro de Regulación Genómica）根据数据反馈的结果，KRAS拥有着比预期更多的变构位点，同时作者在6种结合蛋白中都找到了相关的全新变构位点。当这些位点的氨基酸出现突变时，KRAS蛋白与6种结合蛋白的相互作用会极大减弱，这意味着我们其实拥有着许多潜在可以靶向，且能发挥作用的变构位点。值得一提的是，在这些变构位点中，有一些位于KRAS表面为数不多又容易针对的4个口袋结构中，其中口袋1和口袋2中的突变会阻止KRAS与RAF1结合；口袋3则与KRAS的活性位点距离较远，因此之前较少受到关注，但它实则保持着较高的变构活性；口袋4则位于效应子结合环附近。▲研究发现的多个口袋结构（图片来源：参考资料[1]）而这些区域的微小变化，就能极大地改变KRAS与其他蛋白的相互作用，因此通过靶向这些变构位点就能控制KRAS的异常活性，而不影响健康细胞中的KRAS作用，减少药物的副作用。研究提供的这张KRAS变构位点图谱，也将激发对更多其他蛋白的变构位点研究。研究通讯作者Ben Lehner教授指出，针对变构位点的药物将要比现有药物更安全，也会更有效，而未来我们需要做的就是从这张图谱中挑选出合适的位点。参考资料：[1] The energetic and allosteric landscape for KRAS inhibition, Nature (2023). DOI: 10.1038/s41586-023-06954-0[2] Secret vulnerabilities of cancer's 'Death Star' protein revealed. Retrieved December 19, 2023 from https://medicalxpress.com/news/2023-12-secret-vulnerabilities-cancer-death-star.html本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

临床研究

2023-10-24

·药渡Daily

和誉生物新一代EGFR exon20ins抑制剂国内获临床默示许可

2023年10月24日，根据中国国家药监局药品审评中心（CDE）官网数据显示，和誉生物新一代EGFR exon20ins抑制剂ABSK112胶囊获得临床默示许可。根据公司官网显示，ABSK112对EGFR exon20ins突变覆盖广泛，对野生型EGFR具有更高的选择性及入脑性。临床前对携带EGFR exon20ins突变的小鼠异种移植瘤模型表现出极佳的体内药效。2023年7月ABSK112获得FDA临床研究许可，这是一项首次人体（FIH）、多中心、非随机、开放性的I期试验。此项研究首先在NSCLC患者中进行ABSK112的剂量递增，旨在评价研究药物的安全性、耐受性、药代动力（PK）和初步抗肿瘤活性。药渡数据库检索，目前EGFR Exon20ins非小细胞肺癌（NSCLC）领域国内企业在研产品共14个。来源：药渡数据库和誉生物在研管线根据公司2023年中报显示，目前临床阶段在研产品8个，靶点涵盖：CSF-1R、FGFR、EGFR Exon20、PD-L1（oral）及CXCR4。公司自主开发的小分子CSF-1R抑制剂Pimicotinib已进入关键III期临床，适应症为腱鞘巨细胞瘤（TGCT）。Pimicotinib已在中美两地获得突破性疗法疗法（BTD）认定，同时也获得了EMA重点药品快速审评程序（PRIME）。Pimicotinib一旦获批将成为首个国内企业自主开发上市的高选择性CSF-1R抑制剂。公司临床前研究靶点包括：CD73、FGFR4、EGFR-C797S、KARS及PRAMT5等热门靶点。其中EGFR-C797S抑制剂ABK3376于今年3月，与上海艾力斯医药科技股份有限公司达成授权许可。根据协议条款，艾力斯公司将就此项授权向和誉医药支付最高不超过18,790万美元的首付款、开发及销售里程碑付款以及相应比例净销售额的许可提成费。参考文献1.CDE数据库2.和誉生物官网3.药渡数据库END👇关注药渡数据媒体矩阵

临床3期突破性疗法引进/卖出临床1期