PDF(Pubmed)
Abstract：
Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.
摘要：
甲状旁腺激素1受体（PTH1R）在介导钙稳态和骨骼发育中起关键作用，和异常的PTH1R活性是几种人类疾病的基础。肽PTH1R拮抗剂和反向激动剂在治疗这些疾病方面具有治疗潜力，但它们较差的药代动力学和药效学破坏了它们的体内功效。在这里，我们报道了使用骨架修饰策略来设计一种肽PTH1R抑制剂,该抑制剂在体外和体内表现出作为野生型PTH1R拮抗剂和组成型活性PTH1R-H223R突变体反向激动剂的延长活性.该肽可能对改善PTH1R功能障碍的治疗剂的未来开发感兴趣。
