Medicinal Research Reviews最新文献

英文中文

Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide 令人信服的证据：一氧化碳治疗潜力的关键更新。

IF 10.9 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-30 DOI: 10.1002/med.22116

Nicola Bauer, Qiyue Mao, Aditi Vashistha, Anupamaa Seshadri, Yi-Chieh Nancy Du, Leo Otterbein, Chalet Tan, Mark P. de Caestecker, Binghe Wang

Carbon monoxide (CO) is an endogenous signaling molecule. It is produced via heme degradation by heme oxygenase (HMOX), releasing stoichiometric amounts of CO, iron, and biliverdin (then bilirubin). The HMOX-CO axis has long been shown to offer beneficial effects by modulating inflammation, proliferation and cell death as they relate to tissue and organ protection. Recent years have seen a large number of studies examining CO pharmacology, its molecular targets, cellular mechanisms of action, pharmacokinetics, and detection methods using various delivery modalities including inhaled CO gas, CO solutions, and various types of CO donors. Unfortunately, one widely used donor type includes four commercially available carbonyl complexes with metal or borane, CORM-2 (Ru²⁺), CORM-3 (Ru²⁺), CORM-A1 (BH₃), and CORM-401 (Mn⁺), which have been shown to have minimal and/or unpredictable CO production and extensive CO-independent chemical reactivity and biological activity. As a result, not all “CO biological activities” in the literature can be attributed to CO. In this review, we summarize key findings based on CO gas and CO in solution for the certainty of the active principal and to avoid data contamination resulting from the confirmed or potential reactivities and activities of the “carrier” portion of CORMs. Along a similar line, we discuss interesting potential research areas of CO in the brain including a newly proposed CO/HMOX/dopamine axis and the role of CO in cognitive stimulation and circadian rhythm. This review is critical for the future development of the CO field by steering clear of complications caused by chemically reactive donor molecules.

一氧化碳（CO）是一种内源性信号分子。它是通过血红素加氧酶（HMOX）降解血红素产生的，释放出化学计量量的一氧化碳、铁和胆绿素（然后是胆红素）。长期以来，HMOX-CO轴一直被证明具有调节炎症、增殖和细胞死亡的有益作用，因为它们与组织和器官保护有关。近年来，大量的研究对CO的药理学、分子靶点、细胞作用机制、药代动力学和检测方法进行了研究，这些研究采用了各种给药方式，包括吸入CO气体、CO溶液和各种类型的CO供体。不幸的是，一种广泛使用的供体类型包括四种市售的与金属或硼烷的羰基配合物，CORM-2 (Ru2+), CORM-3 (Ru2+), CORM-A1 （BH3）和CORM-401 (Mn+)，它们已被证明具有最小和/或不可预测的CO生成和广泛的CO独立化学反应活性和生物活性。因此，并非所有文献中的“CO生物活性”都可以归因于CO。在这篇综述中，我们总结了基于CO气体和溶液中的CO的关键发现，以确定活性主体，并避免由于corm的“载体”部分的已确认或潜在反应性和活性而导致的数据污染。与此类似，我们讨论了CO在大脑中有趣的潜在研究领域，包括新提出的CO/HMOX/多巴胺轴以及CO在认知刺激和昼夜节律中的作用。通过避免化学反应性供体分子引起的并发症，这一综述对CO领域的未来发展至关重要。

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引用次数: 0

Harnessing the Power of Natural Products for Targeted Protein Degradation 利用天然产物的力量进行靶向蛋白质降解。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-30 DOI: 10.1002/med.22113

Bo Zhu, Zheng Wu, Yiwen Shou, Kaili Zhao, Qinpei Lu, Jiang-Jiang Qin, Hongwei Guo

Natural products have garnered significant attention due to their complex chemical structures and remarkable pharmacological activities. With inherent recognition capabilities for protein surfaces, natural products serve as ideal candidates for designing proteolysis-targeting chimeras (PROTACs). The utilization of natural products in PROTAC development offers distinct advantages, including their rich chemical diversity, multitarget activities, and sustainable sourcing. This comprehensive review explores the vast potential of harnessing natural products in PROTAC research. Moreover, the review discusses the application of natural degradant technology, which involves utilizing natural product-based compounds to selectively degrade disease-causing proteins, as well as the implementation of computer-aided drug design (CADD) technology in identifying suitable targets for degradation within the realm of natural products. By harnessing the power of natural products and leveraging computational tools, PROTACs derived from natural products have the potential to revolutionize drug discovery and provide innovative therapeutic interventions for various diseases.

天然产物因其复杂的化学结构和显著的药理活性而备受关注。天然产物具有固有的蛋白质表面识别能力，是设计蛋白水解靶向嵌合体（PROTACs）的理想候选者。在PROTAC开发中利用天然产品具有明显的优势，包括其丰富的化学多样性，多目标活动和可持续的采购。这篇全面的综述探讨了在PROTAC研究中利用天然产物的巨大潜力。此外，本文还讨论了自然降解技术的应用，包括利用基于天然产物的化合物选择性地降解致病蛋白质，以及在天然产物领域内确定合适降解靶点的计算机辅助药物设计（CADD）技术的实施。通过利用天然产物的力量和利用计算工具，源自天然产物的PROTACs有可能彻底改变药物发现，并为各种疾病提供创新的治疗干预措施。

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引用次数: 0

The Hsp90β Isoform: An Attractive Target for Drug Development Hsp90β亚型：一个有吸引力的药物开发靶点

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-28 DOI: 10.1002/med.22114

Subhabrata Chaudhury, Terin D'Amico, Brian S. J. Blagg

The beta isoform of 90 kDa heat shock protein (Hsp90β) plays a critical role in maintaining cellular proteostasis by assisting in the folding and refolding of proteins, which is essential for both normal cellular function and stress response. It is constitutively expressed in mammalian cells, differentiating it from the inducible Hsp90α isoform. Hsp90β's involvement in diverse cellular processes, such as signal transduction, cell cycle control, and apoptosis, underscores its significant role in various diseases, including cancer and neurodegenerative disorders. The isoform-specific functions of Hsp90β and its interaction with unique client proteins make it a promising target for therapeutic intervention, particularly in the development of selective inhibitors that avoid the adverse effects observed with pan-Hsp90 inhibitors. This review delves into the structural and functional intricacies of Hsp90β, its role in disease, and the potential for selective drug development.

90kda热休克蛋白（Hsp90β）的β亚型通过协助蛋白质的折叠和再折叠在维持细胞蛋白质稳态中起关键作用，这对正常细胞功能和应激反应都是必不可少的。它在哺乳动物细胞中组成性表达，区别于可诱导的Hsp90α亚型。Hsp90β参与多种细胞过程，如信号转导、细胞周期控制和细胞凋亡，强调了其在多种疾病（包括癌症和神经退行性疾病）中的重要作用。Hsp90β的异构体特异性功能及其与独特客户蛋白的相互作用使其成为治疗干预的有希望的靶点，特别是在开发选择性抑制剂以避免pan-Hsp90抑制剂所观察到的不良反应方面。这篇综述深入探讨了Hsp90β的结构和功能复杂性，它在疾病中的作用，以及选择性药物开发的潜力。

引用次数: 0

The Quinoline Photoremovable Group (PPG) Platform—A Medicinal Chemist's Approach for Photocage Development and Applications 喹啉光移除基（PPG）平台——药物化学家的光笼开发和应用方法。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-12 DOI: 10.1002/med.22111

Bence Kontra, Zoltán Mucsi, Janez Ilaš, Petra Dunkel

Photoremovable protecting groups (PPGs) offer a straightforward solution for the temporary inactivation of biologically active substrates and their subsequent controlled release by light irradiation. Their relatively easy design and mode of application have made them useful tools for studying dynamic biological processes in vitro and in vivo. Recently, there has been a growing body of data investigating their potential application in the development of drug delivery systems. Of the various PPG scaffolds in use, quinoline photocages have a history of about 20 years. The structure-property relationships of quinoline PPGs, as well as alternative multibranch designs based on quinoline monomers have been thoroughly studied both experimentally and theoretically. Therefore, quinoline PPGs serve as a representative study of PPG development, showing how the various applications of quinoline photocages followed the chemical optimization or how the applications drove the chemical design. Since the raison d’être of PPGs lies in their application for light-activated release of various substrates or performing light-activated structural changes in materials, it is crucial to understand how PPGs are selected and utilized by their end-users, who are often not chemists themselves. Therefore, we discuss whether the conclusions drawn from the selected quinoline PPG family could lead to more general insights for the field as whole. As PPG-related applications still rely heavily on a limited number of chemical scaffolds, it is worth considering, what could be the reasons for the slow uptake of novel chemical scaffolds.

光可移除保护基团（PPGs）为生物活性底物的暂时失活及其随后的光照射控制释放提供了一种直接的解决方案。它们相对容易的设计和应用模式使它们成为研究体内和体外动态生物过程的有用工具。最近，有越来越多的数据研究了它们在药物输送系统开发中的潜在应用。在目前使用的各种PPG支架中，喹啉光笼已有大约20年的历史。喹啉PPGs的结构-性能关系以及基于喹啉单体的多分支设计已经在实验和理论上得到了深入的研究。因此，喹啉光笼作为PPG发展的代表性研究，展示了喹啉光笼的各种应用如何遵循化学优化或应用如何驱动化学设计。由于PPGs的être的原因在于它们用于各种底物的光激活释放或在材料中进行光激活结构变化，因此了解PPGs如何被最终用户（通常不是化学家）选择和利用是至关重要的。因此，我们讨论从选定的喹啉PPG家族中得出的结论是否可以为整个领域带来更普遍的见解。由于ppg相关的应用仍然严重依赖于数量有限的化学支架，值得考虑的是，新型化学支架吸收缓慢的原因是什么？

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引用次数: 0

Molecular Tools to Study and Control Dopaminergic Neurotransmission With Light 利用光研究和控制多巴胺能神经传递的分子工具。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-10 DOI: 10.1002/med.22112

Galyna Maleeva, Carlo Matera, Silvia Roda, Alessio Colleoni, Marco De Amici, Pau Gorostiza

Dopaminergic neurotransmission is involved in several important brain functions, such as motor control, learning, reward-motivated behavior, and emotions. Dysfunctions of dopaminergic system may lead to the development of various neurological and psychiatric disorders, like Parkinson's disease, schizophrenia, depression, and addictions. Despite years of sustained research, it is not fully established how dopaminergic neurotransmission governs these important functions through a relatively small number of neurons that release dopamine. Light-driven neurotechnologies, based on the use of small light-regulated molecules or overexpression of light-regulated proteins in neurons, have greatly contributed to the advancement of our understanding of dopaminergic circuits and our ability to control them selectively. Here, we overview the current state-of-the-art of light-driven control of dopaminergic neurotransmission. While we provide a concise guideline for the readers interested in pharmacological, pharmacogenetic, and optogenetic approaches to modulate dopaminergic neurotransmission, our primary focus is on the usage of photocaged and photo-switchable small dopaminergic molecules. We argue that photopharmacology, photoswitchable molecules of varied modalities, can be employed in a wide range of experimental paradigms, providing unprecedent insights into the principles of dopaminergic control, and represent the most promising light-based therapeutic approach for spatiotemporally precise correction of dopamine-related neural functions and pathologies.

多巴胺能神经传递涉及几个重要的大脑功能，如运动控制、学习、奖励动机行为和情绪。多巴胺能系统功能障碍可导致各种神经和精神疾病的发展，如帕金森病、精神分裂症、抑郁症和成瘾。尽管经过多年的持续研究，多巴胺能神经传递如何通过释放多巴胺的相对较少的神经元来控制这些重要的功能还没有完全确定。基于使用小的光调节分子或在神经元中过度表达光调节蛋白的光驱动神经技术，极大地促进了我们对多巴胺能回路的理解和我们有选择性地控制它们的能力。在这里，我们概述了当前的最新技术的光驱动控制多巴胺能神经传递。虽然我们为对调节多巴胺能神经传递的药理学、药物遗传学和光遗传学方法感兴趣的读者提供了简明的指南，但我们的主要重点是光笼化和光可切换小多巴胺能分子的使用。我们认为，光药理学，各种形态的光开关分子，可以应用于广泛的实验范式，提供了对多巴胺能控制原理的前所未有的见解，并代表了最有前途的基于光的治疗方法，用于时空精确校正多巴胺相关的神经功能和病理。

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引用次数: 0

Marine Natural Products in Inflammation-Related Diseases: Opportunities and Challenges 海洋天然产物与炎症相关疾病：机遇与挑战。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-09 DOI: 10.1002/med.22109

Tao Zhang, Zijun Ouyang, Yueran Zhang, Haiyan Sun, Lingdong Kong, Qiang Xu, Jiao Qu, Yang Sun

In recent decades, the potentiality of marine natural products (MNPs) in the medical field has been increasingly recognized. Natural compounds derived from marine microorganisms, algae, and invertebrates have shown significant promise for treating inflammation-related diseases. In this review, we cover the three primary sources of MNPs and their diverse and unique chemical structures and bioactivities. This review aims to summarize the progress of MNPs in combating inflammation-related diseases. Moreover, we cover the functions and mechanisms of MNPs in diseases, highlighting their functions in regulating inflammatory signaling pathways, cellular stress responses, and gut microbiota, among others. Meanwhile, we focus on key technologies and scientific methods to address the current limitations and challenges in MNPs.

近几十年来，海洋天然产物（MNPs）在医学领域的潜力日益得到认可。从海洋微生物、藻类和无脊椎动物中提取的天然化合物在治疗炎症相关疾病方面显示出巨大的希望。本文综述了MNPs的三种主要来源及其多样性和独特的化学结构和生物活性。本文综述了MNPs在抗炎症相关疾病中的研究进展。此外，我们还介绍了MNPs在疾病中的功能和机制，重点介绍了它们在调节炎症信号通路、细胞应激反应和肠道微生物群等方面的功能。同时，我们关注关键技术和科学方法，以解决当前MNPs的局限性和挑战。

引用次数: 0

A Bright Future for Photopharmaceuticals Addressing Central Nervous System Disorders: State of the Art and Challenges Toward Clinical Translation 光药物治疗中枢神经系统疾病的光明未来：技术现状和临床转化的挑战。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-05 DOI: 10.1002/med.22105

Rudolf L. Z. Ganzoni, Sofie S. Bournons, Erick M. Carreira, Dimitri De Bundel, Ilse Smolders

Photopharmacology is an innovative approach that uses light to activate drugs. This method offers the potential for highly localized and precise drug activation, making it particularly promising for the treatment of neurological disorders. Despite the enticing prospects of photopharmacology, its application to treat human central nervous system (CNS) diseases remains to be demonstrated. In this review, we provide an overview of prominent strategies for the design and activation of photopharmaceutical agents in the field of neuroscience. Photocaged and photoswitchable drugs and bioactive molecules are discussed, and an instructive list of examples is provided to highlight compound design strategies. Special emphasis is placed on photoactivatable compounds for the modulation of glutamatergic, GABAergic, dopaminergic, and serotonergic neurotransmission for the treatment of neurological conditions, as well as various photoresponsive molecules with potential for improved pain management. Compounds holding promise for clinical translation are discussed in-depth and their potential for future applications is assessed. Neurophotopharmaceuticals have yet to achieve breakthrough in the clinic, as both light delivery and drug design have not reached full maturity. However, by describing the current state of the art and providing illustrative case studies, we offer a perspective on future opportunities in the field of neurophotopharmacology focused on addressing CNS disorders.

光药理学是一种利用光激活药物的创新方法。这种方法具有高度局部化和精确激活药物的潜力，因此在治疗神经系统疾病方面特别有前景。尽管光药理学前景诱人，但其在治疗人类中枢神经系统（CNS）疾病方面的应用仍有待证实。在这篇综述中，我们将概述神经科学领域设计和激活光药剂的主要策略。文中讨论了光笼化和光开关药物及生物活性分子，并列举了一些具有启发性的例子，以突出化合物设计策略。其中特别强调了用于调节谷氨酸能、GABA 能、多巴胺能和血清素能神经递质以治疗神经系统疾病的光活化化合物，以及具有改善疼痛治疗潜力的各种光致分子。我们深入讨论了有望转化为临床药物的化合物，并对其未来的应用潜力进行了评估。由于光传输和药物设计尚未完全成熟，神经光药物尚未在临床上取得突破。不过，通过描述当前的技术水平并提供说明性案例研究，我们对神经光药理学领域未来的机遇提供了一个视角，该领域的重点是解决中枢神经系统疾病。

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引用次数: 0

Recent Developments in the Optical Control of Adrenergic Signaling 肾上腺素能信号光调控的最新进展。

IF 11.6 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-04-03 DOI: 10.1002/med.22110

Shuang Shi, Yangzhi Cao, Maikel Wijtmans, Henry F. Vischer, Rob Leurs

Adrenoceptors (ARs) play a vital role in various physiological processes and are key therapeutic targets. The advent of optical control techniques, including optogenetics and photopharmacology, offers the potential to modulate AR signaling with precise temporal and spatial resolution. In this review, we summarize the latest advancements in the optical control of AR signaling, encompassing optogenetics, photocaged compounds, and photoswitchable compounds. We also discuss the limitations of current tools and provide an outlook on the next generation of optogenetic and photopharmacological tools. These emerging optical technologies not only enhance our understanding of AR signaling but also pave the way for potential therapeutic developments.

肾上腺素受体（ARs）在多种生理过程中发挥重要作用，是重要的治疗靶点。光控制技术的出现，包括光遗传学和光药理学，提供了以精确的时间和空间分辨率调制AR信号的潜力。本文综述了AR信号光调控的最新进展，包括光遗传学、光笼化化合物和光开关化合物。我们还讨论了现有工具的局限性，并对下一代光遗传学和光药理学工具进行了展望。这些新兴的光学技术不仅增强了我们对AR信号的理解，而且为潜在的治疗发展铺平了道路。

引用次数: 0

Light-Activated Pharmacological Tools for Exploring the Cholinergic System 探索胆碱能系统的光激活药理学工具。

IF 10.9 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-03-23 DOI: 10.1002/med.22108

Alessio Colleoni, Giulia Galli, Clelia Dallanoce, Marco De Amici, Pau Gorostiza, Carlo Matera

Cholinergic transmission plays a critical role in both the central and peripheral nervous systems, affecting processes such as learning, memory, and inflammation. Conventional cholinergic drugs generally suffer from poor selectivity and temporal precision, leading to undesired effects and limited therapeutic efficacy. Photopharmacology aims to overcome the limitations of traditional drugs using photocleavable or photoswitchable ligands and spatiotemporal patterns of illumination. Spanning from muscarinic and nicotinic modulators to cholinesterase inhibitors, this review explores the development and application of light-activated compounds as tools for unraveling the role of cholinergic signaling in both physiological and pathological contexts, while also paving the way for innovative phototherapeutic approaches.

胆碱能传递在中枢和外周神经系统中都起着关键作用，影响学习、记忆和炎症等过程。常规胆碱能药物的选择性和时间精度较差，导致效果不佳，治疗效果有限。光药理学旨在利用光切割或光开关配体和照明的时空模式来克服传统药物的局限性。从毒蕈碱和烟碱调节剂到胆碱酯酶抑制剂，本综述探讨了光激活化合物的发展和应用，作为揭示胆碱能信号在生理和病理背景下的作用的工具，同时也为创新的光疗方法铺平了道路。

引用次数: 0

Danshensu Derivatives: A Series of Promising Drugs With Protective Effects Against Cardiocerebrovascular Diseases and Cancers 丹参素衍生物：一系列具有保护心脑血管疾病和癌症作用的有前景的药物。

IF 10.9 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews

Pub Date : 2025-03-12 DOI: 10.1002/med.22102

Yang Yang, Luyang Du, Huadong Zhao, Ye Zhao, Sha Liao, Zhe Zhang, Shaofei Zhang, Yajun Bai, Xiaohui Zheng

Salvia miltiorrhiza (Danshen in Chinese) is a traditional medicinal plant with an extensive range of cardiocerebrovascular protective effects widely used in China and other Asian countries. Danshensu (DSS) is the most important water-soluble component of Danshen and has significant antioxidant, anti-inflammatory, antiplatelet aggregation, antitumor, and other pharmacological activities. However, DSS has poor fat solubility and is unstable due to its o-phenol hydroxyl and α-hydroxy carboxylic acids. Therefore, it is necessary to develop new DSS derivatives through reasonable structural modifications to obtain new drugs with better activity, preferable stability, and higher bioavailability. Our team has previously investigated the effect of Danshen on chronic diseases. Through nearly two decades of research, we have made considerable research progress on the impact of DSS derivatives on cardiocerebrovascular diseases. Based on the published literature and our previous work, it was confirmed that DSS derivatives have a wide range of cardiocerebrovascular protective and other pharmacological effects. Here, this review summarized recent research progress on DSS derivatives in terms of design, synthesis, pharmacological effects, and molecular mechanisms to provide new insights for further research.

丹参是一种具有广泛心脑血管保护作用的传统药用植物，在中国和其他亚洲国家广泛应用。丹参素（DSS）是丹参中最重要的水溶性成分，具有显著的抗氧化、抗炎、抗血小板聚集、抗肿瘤等药理活性。然而，DSS由于其邻酚羟基和α-羟基羧酸，脂溶性差，不稳定。因此，有必要通过合理的结构修饰，开发新的DSS衍生物，以获得活性更好、稳定性更好、生物利用度更高的新药。我们的团队之前已经研究过丹参对慢性疾病的影响。经过近二十年的研究，我们在DSS衍生物对心脑血管病的影响方面取得了相当大的研究进展。根据已发表的文献和我们之前的工作，证实了DSS衍生物具有广泛的心脑血管保护和其他药理作用。本文从DSS衍生物的设计、合成、药理作用、分子机制等方面综述了近年来的研究进展，以期为今后的研究提供新的思路。

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