更新于：2024-05-01

α2A-AR

肾上腺素能受体α-2a

更新于：2024-05-01

基本信息

别名

alpha-2A-adrenergic receptor、ADRA2、ADRA2A

+ [10]

简介

Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = pindolol.

关联

盐酸利舒地尔/酒石酸溴莫尼定

靶点

ROCK1 x α2A-AR

作用机制

ROCK1抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期2022-09-26

Centhaquine

靶点

ADRA2B x α2A-AR

作用机制

ADRA2B 激动剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

印度

首次获批日期2020-05-14

Cefotiam hexetil hydrochloride

盐酸头孢替安酯

靶点

α2A-AR

作用机制

α2A-AR激动剂

在研机构

北京博时安泰科技发展有限公司 [+1]

原研机构

Takeda Pharmaceutical Co., Ltd.

在研适应症

脓肿 [+19]

非在研适应症

急性支气管炎 [+9]

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期1990-01-01

项与 α2A-AR 相关的临床试验

ACTRN12624000384550 / Not yet recruiting临床2期

A pilot single-centre double-blind randomised controlled trial of centhaquine in the treatment of vasodilatory hypotension in adults admitted to the intensive care unit

开始日期2024-07-01

申办/合作机构

Austin Health

NCT05241067 / Not yet recruiting临床2期

A Multicentric Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of Centhaquine as an Adjuvant to the Standard of Care in COVID-19 Patients With Moderate to Severe Acute Respiratory Distress Syndrome

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus causing coronavirus disease 2019 (COVID-19), which has been a global pandemic since March 2020. According to WHO, more than 289 million cases have been confirmed worldwide, with just over 5.4 million reported deaths as of January 2022. SARS-CoV-2 variants continue to emerge, with the omicron variant causing the increased surge in cases. Currently, Johns Hopkins University of Medicine reports a case fatality rate of 1.5% for the United States. COVID-19 infections may be asymptomatic in some cases, while most cases cause mild to moderate illness with respiratory and flu-like symptoms. However, a significant number of COVID-19 cases develop severe life-threatening illness involving severe pneumonia and acute respiratory distress syndrome (ARDS), requiring admission to the intensive care unit (ICU)
Although there have been breakthroughs in the treatment for COVID-19, most of these are directed at mild-to-moderate disease rather than patients with severe disease on mechanical ventilators. There is still a need for novel and effective treatment options in severe COVID-19 illness with continued vaccine hesitancy, decreased social distancing, and new emerging variants.
Centhaquine is a first-in-class resuscitative agent for the hypovolemic shock that is approved for marketing in India. Centhaquine has been found to be an effective resuscitative agent in rat, rabbit, and swine models of hemorrhagic shock. Its safety and tolerability have been demonstrated in a human phase I study in 25 subjects (CTRI/2014/06/004647). Clinical phase II (CTRI/2017/03/008184) and phase III (CTRI/2019/01/017196) results indicate that centhaquine is a novel first-in-class, highly effective resuscitative agent for hypovolemic shock. Centhaquine provided hemodynamic stability and significantly improved acute respiratory distress syndrome (ARDS) and multiple organ dysfunction score (MODS) in clinical trials conducted in India. A total of 155 patients with hypovolemic shock have been studied (combined phase II and III). Centhaquine is safe and reduced the mortality from 10.71% in patients receiving standard treatment to 2.20% in patients that received centhaquine (odds ratio 5.340; 95% CI 1.270-26.50; P=0.0271). In a phase 3 study of hypovolemic shock, ARDS and MODS were secondary endpoints, and centhaquine reduced both with a significant p-value.

开始日期2024-03-31

申办/合作机构

Pharmazz, Inc.

NCT06262607 / Recruiting临床2期

A Randomized, Double-blind, Vehicle-controlled, Multicenter, Parallel-Design, Phase 2 Study to Assess the Efficacy and Safety of CLE-400 Topical Gel for the Treatment of Chronic Pruritus in Adult Subjects With Notalgia Paresthetica

This is a Phase 2, randomized, double-blind, vehicle-controlled study to assess the efficacy and safety of CLE-400 topical gel for the treatment of chronic pruritus in adult subjects with Notalgia Paresthetica (NP).

开始日期2024-01-29

申办/合作机构

Clexio Biosciences Ltd.初创企业

100 项与 α2A-AR 相关的临床结果

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100 项与 α2A-AR 相关的转化医学

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0 项与 α2A-AR 相关的专利（医药）

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1,676

项与 α2A-AR 相关的文献（医药）

2024-02-16·Scientific reports

Role of Hemigraphis alternata in wound healing: metabolomic profiling and molecular insights into mechanisms.

Article

作者: Rex Devasahayam Arokia Balaya ; Akhina Palollathil ; Sumaithangi Thattai Arun Kumar ; Jaikanth Chandrasekaran ; Shubham Sukerndeo Upadhyay ; Sakshi Sanjay Parate ; M Sajida ; Gayathree Karthikkeyan ; Thottethodi Subrahmanya Keshava Prasad

Hemigraphis alternata (H. alternata), commonly known as Red Flame Ivy, is widely recognized for its wound healing capabilities. However, the pharmacologically active plant components and their mechanisms of action in wound healing are yet to be determined. This study presents the mass spectrometry-based global metabolite profiling of aqueous and ethanolic extract of H. alternata leaves. The analysis identified 2285 metabolites from 24,203 spectra obtained in both positive and negative polarities. The identified metabolites were classified under ketones, carboxylic acids, primary aliphatic amines, steroids and steroid derivatives. We performed network pharmacology analysis to explore metabolite-protein interactions and identified 124 human proteins as targets for H. alternata metabolites. Among these, several of them were implicated in wound healing including prothrombin (F2), alpha-2A adrenergic receptor (ADRA2A) and fibroblast growth factor receptor 1 (FGFR1). Gene ontology analysis of target proteins enriched cellular functions related to glucose metabolic process, platelet activation, membrane organization and response to wounding. Additionally, pathway enrichment analysis revealed potential molecular network involved in wound healing. Moreover, in-silico docking analysis showed strong binding energy between H. alternata metabolites with identified protein targets (F2 and PTPN11). Furthermore, the key metabolites involved in wound healing were further validated by multiple reaction monitoring-based targeted analysis.

2024-02-05·Brain, behavior, and immunity

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice.

Article

作者: Bin Mei ; Xiaoxia Xu ; Juntao Weng ; Yueyue Yang ; Peng Wang ; Gaolin Qiu ; Chi Zhang ; Qunlin Zhang ; Yao Lu ; Xuesheng Liu

BACKGROUND:

Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism.

METHODS:

Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1β, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured.

RESULTS:

CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia.

CONCLUSIONS:

Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.

2024-01-30·BMC neuroscience

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α_2A-adrenergic receptor.

Article

作者: Chaoyong Tian ; Yang Yang ; Renfeng Wang ; Yao Li ; Fei Sun ; Jun Chen ; Dingjun Zha

BACKGROUND:

The cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats.

METHODS:

We explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α_2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL.

RESULTS:

We found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H₂O₂-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α_2A-AR.

CONCLUSION:

These results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α_2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

项与 α2A-AR 相关的新闻（医药）

2024-01-22

·医药观澜

GLP-1新机制发表，可影响大脑认知功能

▎药明康德内容团队编辑在2023年《科学》杂志公布的年度突破中，胰高血糖素样肽-1（GLP-1）激动剂成功登顶，这一疗法标志着科学界在对抗肥胖及其相关并发症的里程碑式突破，也让更多人认识到了GLP-1这个名字。近些年来，以司美格鲁肽、Zepbound为代表的GLP-1药物相继获美国FDA批准用于肥胖症治疗；一款名为retatrutide的三靶点药物更是在2023年的临床试验中取得11个月平均减重24.2%的成绩。图片来源：123RF作为一种关键的代谢调节分子，身体内部的GLP-1主要从肠道L细胞释放，并通过促进胰岛素释放等方式改善血糖。而GLP-1激动剂正是通过模仿天然GLP-1的作用来调节2型糖尿病患者的血糖水平。血糖代谢紊乱除了会影响糖尿病发生，其实还与大脑认知、记忆功能下降有关。临床研究证实，葡萄糖代谢紊乱被认为是导致包括阿尔茨海默病在内诸多神经系统疾病恶化的关键因素之一。但代谢变化与大脑认知功能之间的调节机制仍然有许多谜团待解开。1月18日，清华大学免疫所、医学院曾文文与上海交通大学医学院附属仁济医院周鸿主任医师合作在Neuron期刊发表的新成果发现，“肠道交感神经-L细胞”单元通过调控GLP-1分泌影响机体血糖调控和大脑认知功能。具体来看，交感神经通过抑制L细胞中GLP-1的释放，干扰机体血糖稳态，进而抑制葡萄糖在大脑中的利用，影响认知功能。该发现为深入理解“外周交感神经-内分泌轴”的调控机制、以及拓展GLP-1的临床治疗策略奠定了重要的理论基础。在这项研究中，为了探究神经系统与肠道内分泌细胞之间潜在的互作关系，研究团队首先使用免疫荧光染色和全组织染色检测二者的空间位置。结果显示，在小鼠和人肠道组织中，肠道L细胞都与交感神经呈现密切空间关系。同时，肠道L细胞也呈现出紧邻神经纤维的分布趋势，提示肠道L细胞可接受神经信号的调控，成为串联体液调节与神经调节的桥梁。▲研究示意图（图片来源：研究团队提供）为了探究这一结构单元的功能特性，作者对小鼠的交感神经系统进行活性调控。化学遗传学激活交感神经的小鼠在口服葡萄糖耐受量检测试验（OGTT）中出现异常的血糖升高，同时L细胞内的GLP-1的释放受到抑制，GLP-1R激动剂Exendin-4可极大地抑制交感神经激活后血糖上升的现象。研究进一步采用了腹腔神经节切除术（CGX）、化学性交感神经阻断术以及特定脑区立体定位注射等多种技术手段，对肠道交感神经在时空上进行了更为精准地调控。结果均显示，肠道区域性交感神经通过调控L细胞中GLP-1的分泌影响机体血糖稳态。▲交感神经可以抑制肠道的GLP-1分泌（图片来源：参考资料[1]）由此可见，肠道交感神经作为上游的信号来源。随后，作者开始探究信号下游的传递过程，他们将目光聚焦在肠道上皮中肾上腺素能受体上。研究对小鼠肠道上皮的肾上腺素能受体家族成员表达谱进行了检测，发现其高表达肾上腺素受体α2A（Adra2a），此外单细胞数据分析同样显示，小鼠和人的肠道L细胞中表达Adra2a/ ADRA2A受体。小鼠实验中，作者尝试使用Adra2a受体拮抗剂和在肠道上皮特异性敲除Adra2a受体进行了分析。结果显示，两种方法造成肠道上皮Adra2a信号的特异性抑制或者缺失后，会促进L细胞中GLP-1的释放，并提高小鼠对葡萄糖的耐受性。这种保护作用即使在高脂、高糖饲料喂养下仍然有效。后续借助光声显微成像系统，研究发现通过外周激活GLP-1受体信号可显著增加大脑中的血氧饱和度，并观测到显著的脑血管舒张现象，表明外周来源的GLP-1可能通过调节血管舒张增加向大脑中转运能量物质和氧气的速率以提高大脑中葡萄糖的利用效率，进而影响大脑功能。同时，作者确认操控这一机制可以帮助个体提升大脑认知功能，比如当他们抑制肠交感神经-L细胞单元后，小鼠的空间记忆能力明显提升，能够更好地完成水迷宫任务，这一过程同样依赖GLP-1的参与。总的来看，这项研究发现了一种全新的肠道交感神经-内分泌轴，并阐述了其通过抑制GLP-1分泌实现对血糖和认知功能的调控，为动员肠道分泌内源性GLP-1治疗代谢疾病及相关认知障碍的临床策略提供了潜在靶标。清华大学免疫所、医学院曾文文教授和上海交通大学医学院附属仁济医院周鸿教授为本文共同通讯作者。清华大学医学院、免疫所博士生任文冉为该文第一作者，清华大学医学院博士生陈建辉、李庆庆提供了关键数据，仁济医院王文静、殷霞、庄光磊为本研究作出了重要贡献。研究获得了国家自然科学基金、国家重点研发计划、北京市自然科学基金、清华大学医学院、免疫所和生命科学联合中心的支持。参考资料：[1] Sympathetic nerve-enteroendocrine L cell communication modulates GLP-1 release, brain glucose utilization, and cognitive function.Neuron (2024). DOI: https://doi.org/10.1016/j.neuron.2023.12.012本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「学术经纬」微信公众号留言联系我们。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。

申请上市ASH会议

2024-01-02

·GlobeNewswire-Health Care

BetterLife Announces Closing of Convertible Debentures For Further Development of BETR-001

VANCOUVER, British Columbia, Jan. 02, 2024 (GLOBE NEWSWIRE) -- BetterLife Pharma Inc. (“BetterLife” or the “Company”) (CSE: BETR / OTCQB: BETRF / FRA: NPAU), an emerging biotech company focused on the development and commercialization of cutting-edge treatments for mental disorders, is pleased to announce the closing of $300,000 convertible debentures to further advance the development its lead compound, BETR-001. BETR-001 is BetterLife’s proprietary 2-bromo-LSD, a non-hallucinogenic derivative of lysergic acid diethylamide (LSD). Ahmad Doroudian, the CEO of BetterLife said, “We will use these funds to complete additional BETR-001 IND-enabling studies required by the FDA as well as releasing of GMP drug substance that can be used in future clinical trials. Completion of each study gets BetterLife closer to submission of the IND and start of human clinical trials. Our 2023 published and un-published preclinical efficacy studies all support that BETR-001 will be active in treating psychiatric disorders like other 5HT-2A receptor agonist psychedelics with excellent safety profile. The de-risked profile of BETR-001 is further supported by the fact that 2-bromo-LSD has been in human studies in the 1950s, and its non-hallucinogenic nature, and safety and tolerability in humans confirmed.” He further added, “What makes BETR-001 unique is that it is not only de-risked, but it also has robust intellectual proprietary protection. We are excited to be able to bring this novel new treatment to patients with various psychiatric and neurological disorders in the near future.” BetterLife issued a total of $300,000 10% convertible debentures (the “Convertible Debentures”) which mature on June 30, 2025. The Convertible Debentures are convertible at the option of the holder into units of the Company, consisting of one common share and one share purchase warrant, at a conversion price of $0.10 per unit. Each share purchase warrant will have an exercise price of $0.10 and will expire on December 31, 2025. Dr. Ahmad Doroudian, Chief Executive Officer of the Company, subscribed for a total of $125,000 Convertible Debentures. The participation of Dr. Doroudian in the private placement constituted a “related party transaction” as defined under Multilateral Instrument 61-101 (“MI 61-101“). The issuance to the insider was exempt from the formal valuation requirements of MI 61-101 by virtue of the exemption contained in section 5.5(b) as none of the securities of the Company are listed on a specified stock exchange. The transaction is exempt from the minority shareholder approval requirements of MI 61-101 by virtue of exemption contained in section 5.7(a) of MI 61-101. At the time the transaction was agreed to, neither the fair market value of, nor the fair market value of the consideration for, the transaction, insofar as it involves interested parties, exceeded 25% of the Company’s market capitalization. The Company did not file a material change report at least 21 days prior to the expected closing of the Convertible Debentures as Dr. Doroudian’s participation was not determined at that time. About BetterLife Pharma BetterLife Pharma Inc. is an emerging biotechnology company primarily focused on developing and commercializing two compounds, BETR-001 and BETR-002, to treat neuro-psychiatric and neurological disorders. BETR-001, which is in preclinical and IND-enabling studies, is a non-hallucinogenic and non-controlled LSD derivative in development and it is unique in that it is unregulated and therefore can be self-administered. BetterLife’s synthesis patent for BETR-001 eliminates regulatory hurdles and its pending patent, for composition and method of use, covers treatment of major depressive disorder, anxiety disorder and neuropathic pain and other neuro-psychiatric and neurological disorders. BETR-002, which is in preclinical and IND-enabling studies, is based on honokiol, the active anxiolytic ingredient of magnolia bark. BetterLife’s pending method of use and formulations patent covers treatment of anxiety related disorders including benzodiazepine dependency. BetterLife also owns a drug candidate for the treatment of viral infections such as COVID-19 and is in the process of seeking strategic alternatives for further development. For further information, please visit BetterLife Pharma. BetterLife Pharma Inc. Contact Information David Melles, Investor Relations ManagerEmail: David.Melles@blifepharma.comPhone: 1-778-887-1928 Cautionary Note Regarding Forward-Looking Statements No securities exchange has reviewed nor accepts responsibility for the adequacy or accuracy of the content of this news release. This news release contains forward-looking statements relating to product development, licensing, commercialization and regulatory compliance issues and other statements that are not historical facts. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expects” and similar expressions. All statements other than statements of historical fact, included in this release are forward-looking statements that involve risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the failure to satisfy the conditions of the relevant securities exchange(s) and other risks detailed from time to time in the filings made by the Company with securities regulations. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management at the time of preparation, may prove to be incorrect and actual results may differ materially from those anticipated. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date of this news release and the Company will update or revise publicly any of the included forward-looking statements as expressly required by applicable law.

2023-07-23

·医药观澜

盘点13个潜在“first-in-class”新药靶点

▎药明康德内容团队编辑《自然》子刊Nature Reviews Drug Discovery曾指出，每个“first-in-class”药物的上市多有赖于创新、有效药物靶点的发现，而这也是驱动疾病疗法产生根本性突破的源头。药明康德内容团队检视今年6月发布于国际知名科学期刊的研究，整理了具转化潜力的多项潜在新药靶点，供生物医学产业作为创新研发的参考。限于篇幅，仅针对部分潜在靶点进行介绍。药明康德内容团队整理靶点：MAdCAM-1应用：癌症免疫监测期刊/PMID：《科学》/ 37289890发现：已过发现当癌症病患在接受免疫检查点阻断（ICB）疗法治疗前使用抗生素，然后在治疗开始前停药时，会导致免疫检查点阻断疗法的疗效降低，因此有假说认为患者体内的细菌可能影响其治疗反应。在此研究中，科学发现接受抗生素治疗后的小鼠肠道内肠梭菌（Enterocloster species）的重新定植会导致整合素α4β7配体MAdCAM-1的表达下调。由于MAdCAM-1有助于T细胞（Tr17细胞）的免疫抑制亚群保留在肠道中，因此其表达下调会导致Tr17细胞转移到肿瘤和肿瘤引流淋巴结，进而降低免疫检查点阻断治疗的疗效。此外，研究人员还发现在接受免疫治疗的肾、膀胱和肺癌患者中，其血液中可溶性MAdCAM-1的低水平与其肠道微生物群失调以及患者不良的临床结局相关。因此调控癌症患者体内或肠道中MAdCAM-1水平有望改善免疫疗法在这类癌症患者的疗效。▲MAdCAM-1为癌症免疫监测的肠道免疫检查点（图片来源：参考资料[1]）靶点：α2-AR应用：改善肿瘤免疫疗法期刊/PMID：《自然》/ 37286594发现：免疫检查点阻断疗法作为单药治疗癌症患者的效果通常不理想，因此常需要通过与其他化合物作为组合疗法来使用，这些化合物能够降低肿瘤微环境中的免疫抑制。科学家发现，α2-肾上腺素能受体（α2-AR）激动剂作为单药治疗时，在多种免疫活性肿瘤模型（包括ICB耐药模型）中具有非常强的抗肿瘤活性，但在免疫缺陷模型中则没有。当科学家使用α2-AR拮抗剂或敲除小鼠的Adra2a基因（编码α2a-AR）时，α2-AR激动剂的抗肿瘤作用会被逆转，显示激动剂靶向宿主细胞而非肿瘤细胞。此外，接受治疗的小鼠肿瘤中浸润的T淋巴细胞增加，髓系抑制细胞则凋亡、减少。单细胞RNA测序分析发现巨噬细胞和T细胞中的先天和适应性免疫反应通路产生上调。在Adra2a敲除小鼠中的研究显示，激动剂直接作用于巨噬细胞，增加其活化T淋巴细胞的能力。因此靶向α2-AR的激动剂或可提高癌症免疫治疗的临床疗效。靶点：MBOAT1/2应用：乳腺癌/前列腺癌期刊/PMID：《细胞》/ 37267948发现：铁死亡（ferroptosis）是由铁依赖性磷脂过氧化作用所驱动的细胞死亡过程，与多种疾病有关。抑制铁死亡主要有两种监测机制：一种由催化磷脂过氧化物还原的谷胱甘肽过氧化物酶4（GPX4）介导，另一种由产生具有自由基捕获抗氧化活性代谢物的酶（如FSP1）介导。在这项研究中，科学家通过全基因组CRISPR筛选与后续机制研究发现，磷脂修饰酶MBOAT1和MBOAT2是铁死亡的抑制因子。MBOAT1/2通过重塑细胞磷脂谱来抑制铁死亡，且其铁死亡监测功能独立于GPX4或FSP1。MBOAT1和MBOAT2分别受雌激素受体（ER）和雄激素受体（AR）控制转录上调。科学家发现ER或AR拮抗剂加上诱导铁死亡的组合疗法可显著抑制ER+乳腺癌和AR+前列腺癌的生长，即使肿瘤对单药激素治疗具耐药性亦然。▲抑制MBOAT1/2促进铁死亡（图片来源：参考资料[3]）靶点：ALPL-1应用：骨肉瘤（CAR-T疗法靶点）期刊/PMID：Nature Communications / 37291203发现：骨肉瘤（OS）多发生与儿童和年轻成人中，其中转移性和复发性肿瘤患者的结局较差。由于肿瘤内异质性和潜在靶向蛋白的大量脱靶表达，与其他癌症类型相较，免疫治疗对于OS患者的疗效有限。在此研究中，科学家开发了靶向一种碱性磷酸酶亚型ALPL-1的嵌合抗原受体（CAR）T细胞。ALPL-1在原发性和转移性OS中皆具高度且具特异性地表达。实验证实，这类CAR-T细胞可在体外，以及原发性和转移性OS的原位小鼠模型中，有效介导对ALPL阳性细胞的细胞毒性，并且对造血干细胞或健康组织不产生不在预期中的毒性。靶点：VANGL2应用：病毒性传染病期刊/PMID：Science Advances / 37352355发现：严格控制1型干扰素（IFN-I）信号是对抗病毒感染产生强效先天性免疫应答的关键，然而其潜在的分子机制仍不明确。科学家发现在水泡性口炎病毒（VSV）感染过程中，VANGL2蛋白为一IFN诱导的负反馈调节因子，可抑制IFN-I信号。小鼠髓样细胞VANGL2的特异性缺失会增强抵抗VSV感染的IFN-I信号，提升小鼠存活率。这些发现显示靶向VANGL2可能是治疗病毒感染性疾病的潜在临床靶点。靶点：MAP1B应用：脆性X综合征（FXS）/自闭症谱系障碍（ASD）期刊/PMID：Nature Communications / 37365192发现：在此篇研究中，研究人员发现脆性X信使核糖核蛋白1蛋白（FMRP）的缺乏会导致发育中的人和非人灵长类皮层神经元微管相关蛋白1B（MAP1B）升高。当健康人类神经元中MAP1B基因的激活或自闭症谱系障碍（ASD）患者神经元中MAP1B基因的三倍化，皆会抑制个体的形态和生理成熟。实验显示，成年雄性小鼠前额叶皮质兴奋性神经元Map1b的激活会损害其社会行为能力。当敲除MAP1B基因时，可逆转离体ASD和FXS患者人脑组织中，因缺乏FMRP而导致的神经元缺陷。因此靶向MAP1B可能是治疗FXS和ASD患者的潜在靶点。靶点：USP25应用：肝损伤期刊/PMID：Nature Communications / 37339955发现：核因子红系2相关因子2（NRF2）是一种负责启动抗氧化基因表达程序，以对抗氧化应激反应的转录因子。在非应激条件下，CUL3 E3泛素连接酶的接头蛋白KEAP1介导NRF2的泛素化和降解。研究人员发现去泛素化酶USP25可直接与KEAP1结合，阻止KEAP1自身的泛素化和降解。在没有Usp25或去泛素化酶被抑制的情况下，KEAP1的表达下调，进而使得NRF2水平保持稳定，使细胞更容易对氧化应激作出反应。在对乙酰氨基酚（APAP）过量诱导的氧化性肝损伤雄性小鼠模型中，无论是在遗传学还是药理学上抑制Usp25，都大大降低小鼠的肝损伤，进而降低致死剂量APAP导致的死亡。▲抑制USP25降低小鼠因过量乙酰氨基酚造成的肝损伤（图片来源：参考资料[7]）参考资料：（可上下滑动查看） [1] Fidelle, Marine et al. “A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.” Science (New York, N.Y.) vol. 380,6649 (2023): eabo2296. doi:10.1126/science.abo2296[2] Zhu, Jingjing et al. “Tumour immune rejection triggered by activation of α2-adrenergic receptors.” Nature vol. 618,7965 (2023): 607-615. doi:10.1038/s41586-023-06110-8[3] Liang, Deguang et al. “Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.” Cell vol. 186,13 (2023): 2748-2764.e22. doi:10.1016/j.cell.2023.05.003[4] Mensali, Nadia et al. “ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma.” Nature communications vol. 14,1 3375. 8 Jun. 2023, doi:10.1038/s41467-023-39097-x[5] Hu, Zhiqiang et al. “VANGL2 inhibits antiviral IFN-I signaling by targeting TBK1 for autophagic degradation.” Science advances vol. 9,25 (2023): eadg2339. doi:10.1126/sciadv.adg2339[6] Guo, Yu et al. “Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.” Nature communications vol. 14,1 3801. 26 Jun. 2023, doi:10.1038/s41467-023-39337-0[7] Cai, Changzhou et al. “USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice.” Nature communications vol. 14,1 3648. 20 Jun. 2023, doi:10.1038/s41467-023-39412-6本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号留言联系我们。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。

免疫疗法临床结果微生物疗法