Surfactant-modified parathyroid hormone fragments with high potency and prolonged action: Structure-informed design using glycolipid surfactant conjugation,Peptide Science

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Surfactant-modified parathyroid hormone fragments with high potency and prolonged action: Structure-informed design using glycolipid surfactant conjugation
Peptide Science ( IF 1.5 ) Pub Date : 2021-03-15 , DOI: 10.1002/pep2.24225
John J. Nestor ₁ , Wei Wang ₂

Affiliation

The pharmaceutical properties of peptides (high potency and specificity with low toxicity) make them an attractive therapeutic class but typically short duration of action and low bioavailability can limit their usefulness. Here, we begin evaluation of a new class of peptide modification, glycolipid surfactant conjugation, designed to extend the half-life of peptide therapeutics. This work illustrates ease of synthesis and conjugation, range of modulation of pharmacokinetic/pharmacodynamic behavior and acceptability in vivo of this approach. Proof of concept used parathyroid hormone and showed that an N-terminal fragment can be modified, informed by the parathyroid hormone receptor x-ray structure, to produce high potency, enhanced intrinsic efficacy and prolonged action in vivo. This suggests daily (hypoparathyroidism) or weekly (osteoporosis) administration with biological sequelae (stem cell maturation to osteoblasts) throughout the week. Compound 7 was chosen for advanced study. Exploration of the physical properties and development potential of glycolipid surfactant-modified peptides are underway with additional peptide therapeutics.

中文翻译：

具有高效力和长效作用的表面活性剂修饰的甲状旁腺激素片段：使用糖脂表面活性剂结合的结构信息设计

肽的药物特性（高效能和特异性低毒性）使它们成为一种有吸引力的治疗类别，但通常作用时间短和生物利用度低会限制它们的用途。在这里，我们开始评估一类新的肽修饰，糖脂表面活性剂缀合，旨在延长肽疗法的半衰期。这项工作说明了这种方法的合成和结合的容易性、药代动力学/药效学行为的调节范围和体内可接受性。概念证明使用甲状旁腺激素，并表明可以根据甲状旁腺激素受体 X 射线结构对 N 末端片段进行修饰，以产生高效力、增强内在功效和延长体内作用. 这表明每天（甲状旁腺功能减退症）或每周（骨质疏松症）给药，并在整个星期内产生生物后遗症（干细胞成熟为成骨细胞）。选择化合物7进行高级研究。正在探索糖脂表面活性剂修饰肽的物理特性和开发潜力，并使用其他肽疗法。

更新日期：2021-03-15

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