Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1–84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1–84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1–34 analogue by increasing its affinity to albumin. Three PTH1–34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1–34 variants by using a solid–liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1–34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1–84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.

中文翻译：

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发现用于治疗甲状旁腺功能减退症的长效甲状旁腺激素 1-34 类似物

甲状旁腺功能减退症（HP）是一种罕见的疾病，临床表现为低钙血症和高磷血症，由甲状旁腺激素（PTH）分泌不足或缺乏引起。HP 患者的常规治疗包括大量补充钙和维生素 D。2015 年，美国食品和药物管理局批准 PTH1-84 作为常规治疗无法很好控制的 HP 患者的辅助药物。然而，PTH1-84 疗法需要每天注射一次，导致患者依从性差。本研究的目的是通过增加其对白蛋白的亲和力来开发长效 PTH1-34 类似物。通过用精氨酸取代三个赖氨酸 (Lys) 残基中的两个产生三个 PTH1-34 变体，在每个序列中保留一个 Lys 作为修饰位点。一系列侧链，体外生物活性和白蛋白亲和力测试用于筛选这些新的 PTH1-34 类似物。最后，从 69 种合成的类似物中选择 Lys27-AAPC 作为候选治疗化合物，因为它保留了效力并表现出高的白蛋白结合能力。在药效学实验中，相对于 PTH1-84，Lys27-AAPC 在血清钙升高方面表现出增强和延长的功效。此外，还开发了一种含有 Lys27-AAPC 的注射用冻干粉，用于进一步测试，并代表了一种潜在的长效 HP 治疗方法。