Abstract:
Captopril is a thiol drug, widely used for the management of hypertension and cardiovascular diseases. Reactive thiols are found to covalently modify the cysteines of plasma proteins and affect their structure and function. Human serum albumin (HSA) is prone to undergo modification by various low molecular weight compounds, including drugs. Cysteine34 (Cys34) in HSA has a free thiol group with antioxidant properties, considered to be the most redox-sensitive amino acid in plasma. Through mass-spectrometric analysis, we demonstrate for the first time that captopril forms a disulfide adduct at Cys34 residue and increases the protease susceptibility of HSA to trypsin. As evidenced by our biophysical and electron microscopy studies, HSA undergoes structural alteration, aggregation and morphological changes when treated with different captopril concentrations. Molecular dynamics studies further revealed the regions of secondary structural changes in HSA due to disulfide adduct formation by captopril at Cys34. It also elucidated the residues involved in the noncovalent interactions with captopril. It is envisaged that structural change in HSA may influence the efficacy of drug delivery as well as its own biological function. These findings may thus provide significant insights into the field of pharmacology intriguing further investigation into the effects of long-term captopril treatment.
摘要:
卡托普利是一种巯基药物,广泛用于高血压和心血管疾病的管理。发现反应性硫醇共价修饰血浆蛋白的半胱氨酸并影响其结构和功能。人血清白蛋白(HSA)容易受到各种低分子量化合物的修饰,包括毒品。HSA中的半胱氨酸34(Cys34)具有具有抗氧化性能的游离巯基,被认为是血浆中对氧化还原最敏感的氨基酸。通过质谱分析,我们首次证明卡托普利在Cys34残基形成二硫键加合物,并增加HSA对胰蛋白酶的蛋白酶敏感性。正如我们的生物物理和电子显微镜研究所证明的那样,HSA经历了结构改变,用不同浓度的卡托普利处理时的聚集和形态变化。分子动力学研究进一步揭示了由于卡托普利在Cys34处形成二硫键加合物而导致的HSA二级结构变化区域。它还阐明了与卡托普利非共价相互作用中涉及的残基。据设想,HSA的结构变化可能影响药物递送的功效以及其自身的生物学功能。因此,这些发现可能为药理学领域提供了重要的见解,从而对长期卡托普利治疗的效果进行了进一步的研究。