Extracellular Aldehyde Sensing Probes for In Vivo Imaging.

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yingying Ning, Eman A Akam-Baxter, Peter Caravan
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引用次数: 0

Abstract

ConspectusCarbonyl-ligation reactions are considered to be largely bioorthogonal due to the rarity of ketones and aldehydes in normal mammalian biology, especially in the extracellular space. However, during development, in wound healing, or in response to many disease conditions, certain extracellular matrix (ECM) proteins can be post-translationally modified by lysyl oxidases to contain aldehyde-bearing side chains. In many diseases, accelerated ECM production is a part of a process called fibrosis (scarring of tissue), and about half of the deaths in the industrialized world arise from disease with a fibrotic component. During fibrogenesis (active fibrosis), lysyl oxidases are upregulated, catalyzing the oxidation of lysine residues on ECM proteins to form lysine aldehyde (allysine, LysAld). LysAld undergoes condensation reactions with other LysAld or Lys residues of adjacent collagens to cross-link proteins. Despite the centrality of fibrogenesis in development and in so many diseases, there is a general lack of tools to noninvasively detect and quantify fibrogenesis in humans or in animal models. Our group used rational design to develop molecular probes for LysAld to enable the detection, staging, and treatment monitoring of fibrogenesis. In this Account, we summarize our design strategies and validation methods of LysAld targeting probes for applications in a wide range of diseases with a fibroproliferative component.The LysAld concentrations exhibit distinct organ- and tissue-specific variations in the progression of fibrogenesis. To increase the sensitivity of LysAld probes, we systematically optimized the probe structures to modulate the kinetics of aldehyde condensation reactions and the reverse hydrolysis reaction, molecular hydrophilicity, pharmacokinetics, and elimination. Incorporating electron-withdrawing groups, acidic moieties, and dual-binding ligands significantly enhanced the condensation rates. Combining these strategies with signal amplification by designing "off-on" probes, we extended the probe applicability from organs of high LysAld levels (lung) to low-concentration systems (liver, tumor, and cardiac tissues). Reducing the hydrolysis rate of the probe-LysAld adduct extended the imaging window and permitted the specific detection of LysAld in the kidneys. Importantly, our design strategies demonstrate multimodal compatibility, validated through magnetic resonance imaging, positron emission tomography, and fluorescence imaging platforms. The multiscale detection capability in different imaging modalities (cellular to in vivo) provides critical spatial-temporal insights into fibroproliferative disease dynamics in different species and tissues, including onset, progression, and therapeutic response. While this Account focuses on the design of molecular probes for LysAld, the strategies employed here establish a generalizable framework for molecular probe development with broad applicability in chemical biology and diagnostic imaging.

用于体内成像的细胞外醛传感探针。
羰基连接反应被认为在很大程度上是生物正交的,因为在正常的哺乳动物生物学中,尤其是在细胞外空间中,酮和醛是罕见的。然而,在发育过程中,在伤口愈合或对许多疾病的反应中,某些细胞外基质(ECM)蛋白可以被赖氨酸氧化酶在翻译后修饰,以含有含醛的侧链。在许多疾病中,加速的ECM生成是称为纤维化(组织瘢痕形成)过程的一部分,工业化世界中大约一半的死亡是由具有纤维化成分的疾病引起的。在纤维形成(活动性纤维化)过程中,赖氨酸氧化酶被上调,催化ECM蛋白上赖氨酸残基的氧化形成赖氨酸醛(allysine, LysAld)。LysAld与其他LysAld或邻近胶原的lysd残基发生缩合反应,形成交联蛋白。尽管纤维发生在发育和许多疾病中处于中心地位,但在人类或动物模型中普遍缺乏无创检测和量化纤维发生的工具。我们的团队采用合理的设计来开发LysAld分子探针,以实现纤维发生的检测、分期和治疗监测。在这篇文章中,我们总结了我们的LysAld靶向探针的设计策略和验证方法,用于广泛的具有纤维增殖成分的疾病。LysAld浓度在纤维形成过程中表现出明显的器官和组织特异性变化。为了提高LysAld探针的灵敏度,我们系统地优化了探针结构,以调节醛缩合反应和反水解反应的动力学、分子亲水性、药代动力学和消除。加入吸电子基团、酸性基团和双结合配体显著提高了缩合速率。将这些策略与设计“off-on”探针的信号放大相结合,我们将探针的适用性从高LysAld水平的器官(肺)扩展到低浓度的系统(肝脏、肿瘤和心脏组织)。降低探针-LysAld加合物的水解速率延长了成像窗口,并允许特异性检测肾脏中的LysAld。重要的是,我们的设计策略展示了多模态兼容性,通过磁共振成像、正电子发射断层扫描和荧光成像平台进行了验证。不同成像方式(细胞到体内)的多尺度检测能力为不同物种和组织中的纤维增生性疾病动力学提供了关键的时空洞察,包括发病、进展和治疗反应。虽然本报告侧重于LysAld分子探针的设计,但本文采用的策略为分子探针的开发建立了一个可推广的框架,在化学生物学和诊断成像中具有广泛的适用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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