Institute for Pharmacy, Pharmaceutical Chemistry, Department of Chemistry and Pharmacy, University of Innsbruck, Innrain 80/82, Innsbruck A-6020, Austria.
Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare, Traversa La Crucca 3, Sassari 07040, Italy.
Inorg Chem. 2024 Sep 23;63(38):17785-17796. doi: 10.1021/acs.inorgchem.4c02683. Epub 2024 Sep 12.
Investigating the speciation of vanadium complexes in the presence of potential biomolecular targets under physiological conditions remains challenging, and further experimental techniques are needed to better understand the mechanism of action of potential metallodrugs. The interaction of two model peptides (angiotensin I and angiotensin II) with three well-known oxidovanadium(IV) compounds with antidiabetic and/or anticancer activity, [VO(pic)(HO)], [VO(ma)], and [VO(dhp)] (where pic, ma, and dhp are picolinate, maltolate, and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate anions, respectively), was investigated by ESI-MS/MS (electrospray ionization tandem mass spectrometry) and complemented by EPR (electron paramagnetic resonance) spectroscopy measurements and theoretical calculations at the DFT (density functional theory) level. The results demonstrated that vanadium-peptide bonds are preserved after HCD (higher energy collisional dissociation) fragmentation, allowing for the identification of binding sites through a detailed analysis of the fragmentation spectra. Angiotensin I (AT1) and angiotensin II (AT2) exhibited different coordination behaviors. AT1, with two His residues (His6, His9), prefers to form [AT1 + VOL] adducts with both histidine residues coordinated to the metal ion, while AT2, which has only His6, can bind the metal in a monodentate fashion, forming also [AT2 + VOL] adducts. Insights from this study pave the way to ESI-MS/MS investigations of more complex systems, including target proteins and further development of vanadium-based drugs.
在生理条件下研究钒配合物在潜在生物分子靶标存在下的形态仍然具有挑战性，需要进一步的实验技术来更好地理解潜在金属药物的作用机制。两种模型肽（血管紧张素 I 和血管紧张素 II）与三种具有抗糖尿病和/或抗癌活性的已知氧化钒（IV）化合物[VO(pic)(HO)]、[VO(ma)]和[VO(dhp)]（其中 pic、ma 和 dhp 分别为吡啶酸、麦芽糖酸和 1,2-二甲基-3-羟基-4(1H)-吡啶酮阴离子）的相互作用通过 ESI-MS/MS（电喷雾串联质谱）进行了研究，并通过 EPR（电子顺磁共振）光谱测量和 DFT（密度泛函理论）水平的理论计算进行了补充。结果表明，在 HCD（更高能量碰撞解离）碎裂后，钒-肽键得以保留，通过对碎裂光谱的详细分析，可以确定结合位点。血管紧张素 I（AT1）和血管紧张素 II（AT2）表现出不同的配位行为。具有两个 His 残基（His6、His9）的 AT1 优先与两个组氨酸残基与金属离子配位形成[AT1 + VOL]加合物，而只有 His6 的 AT2 可以以单齿配位方式与金属结合，也形成[AT2 + VOL]加合物。这项研究的结果为更复杂系统（包括靶蛋白）的 ESI-MS/MS 研究铺平了道路，并进一步开发了基于钒的药物。
