当前位置: X-MOL 学术J. Am. Chem. Soc. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Tailored Chemical Reactivity Probes for Systemic Imaging of Aldehydes in Fibroproliferative Diseases
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-08-17 , DOI: 10.1021/jacs.3c04964
Hua Ma 1 , Iris Y Zhou 1 , Y Iris Chen 1 , Nicholas J Rotile 1 , Ilknur Ay 1 , Eman A Akam 1 , Huan Wang 1 , Rachel S Knipe 2 , Lida P Hariri 2, 3 , Caiyuan Zhang 1 , Matthew Drummond 2 , Pamela Pantazopoulos 1 , Brianna F Moon 1 , Avery T Boice 1 , Samantha E Zygmont 1 , Jonah Weigand-Whittier 1 , Mozhdeh Sojoodi 4 , Romer A Gonzalez-Villalobos 5 , Michael K Hansen 5 , Kenneth K Tanabe 4 , Peter Caravan 1
Affiliation  

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small-molecule magnetic resonance probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis non-invasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that, for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, makes them strong candidates for clinical translation.

中文翻译:


用于纤维增生性疾病中醛的全身成像的定制化学反应性探针



在纤维增殖期间,通过细胞外基质蛋白上的赖氨酸残基氧化形成醛赖氨酸,形成与蛋白质相关的细胞外醛。在这里,我们报告了三种基于 Mn(II) 的小分子磁共振探针,它们含有 α 效应亲核试剂,可在体内靶向赖氨酸并报告组织纤维发生。我们采用合理的设计方法来开发开启探针,其靶向时的弛豫度提高了 4 倍。通过系统醛追踪方法评估了醛缩合速率和水解动力学对探针在小鼠模型中无创检测组织纤维发生的性能的影响。我们表明,对于高度可逆的结扎,解离率是体内效率的更强预测因子,从而能够对整个肺的肺纤维发生进行组织学验证的三维表征。这些探针的排他性肾脏消除允许对肝纤维化进行快速成像。通过与赖氨酸形成肟键来降低水解速率,从而实现肾纤维发生的延迟相位成像。这些探针的成像功效,加上它们从体内快速、完全消除,使它们成为临床转化的有力候选者。
更新日期:2023-08-17
down
wechat
bug