Aghazadeh-Habashi Ali, Khajehpour Sana
College of Pharmacy, Idaho State University, Pocatello, ID, USA.
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Leonard Hall 212, Pocatello, ID, 83209-8288, USA.
Amino Acids. 2021 May;53(5):653-664. doi: 10.1007/s00726-021-02972-2. Epub 2021 Mar 31.
The renin-angiotensin system (RAS) has a central role in renal and cardiovascular homeostasis. Angiotensin-(1-7) (Ang1-7), one of the RAS active peptides, exerts beneficial effects through different mechanisms. These biological actions suggest that Ang1-7 is an effective therapeutic agent for treating various diseases associated with activated RAS. However, its short half-life and poor pharmacokinetics restrict its therapeutic utility. Our laboratory has successfully synthesized and characterized an Ang1-7 conjugate (Ang Conj.) with a prolonged half-life and improved pharmacokinetics profile. The Ang Conj. has been prepared by PEGylation of Ang1-7 and conjugation with a bisphosphonate using solid-phase peptide synthesis and characterized by HPLC and mass spectrometer. The compound's stability has been tested in different storage conditions. The bone binding capacity was evaluated using a hydroxyapatite assay. Pharmacokinetic and tissue distribution studies were performed using iodinated peptides in rats. Ang Conj. was synthesized with > 90% purity. Bone mineral affinity testing showed Ang Conj. exhibited significantly higher bone mineral affinity than Ang1-7. The Ang Conj. remained stable for more than a month using all tested storage conditions. The Ang Conj. demonstrated higher affinity to bone, a longer half-life, and better bioavailability when compared with the native peptide. These results support that conjugation of Ang1-7 with bisphosphonate enables it to utilize bone as a reservoir for the sustained delivery of Ang1-7 to maintain therapeutic plasma levels. High chemical stability and about five to tenfold prolongation of Ang Conj. plasma half-life after administrations into rats proves the effectiveness of our approach.
肾素-血管紧张素系统（RAS）在肾脏和心血管稳态中起核心作用。血管紧张素-（1-7）（Ang1-7）是RAS活性肽之一，通过不同机制发挥有益作用。这些生物学作用表明Ang1-7是治疗与活化RAS相关的各种疾病的有效治疗剂。然而，其半衰期短和药代动力学不佳限制了其治疗效用。我们实验室已成功合成并表征了一种半衰期延长且药代动力学特征改善的Ang1-7缀合物（Ang Conj.）。Ang Conj.是通过对Ang1-7进行聚乙二醇化并使用固相肽合成与双膦酸盐缀合而制备的，并通过高效液相色谱和质谱仪进行表征。该化合物的稳定性已在不同储存条件下进行测试。使用羟基磷灰石测定法评估骨结合能力。使用碘化肽在大鼠中进行药代动力学和组织分布研究。Ang Conj.的合成纯度>90%。骨矿物质亲和力测试表明，Ang Conj.表现出比Ang1-7显著更高的骨矿物质亲和力。在所有测试的储存条件下，Ang Conj.保持稳定超过一个月。与天然肽相比，Ang Conj.对骨具有更高的亲和力、更长的半衰期和更好的生物利用度。这些结果支持将Ang1-7与双膦酸盐缀合可使其利用骨作为持续递送Ang1-7以维持治疗性血浆水平的储存库。高化学稳定性以及将Ang Conj.注射到大鼠体内后血浆半衰期延长约五到十倍证明了我们方法的有效性。
