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骨干修饰提供了一种长效的致病性、组成性激活 PTH1R 变体的反向激动剂。

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

机构信息

Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.

Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.

出版信息

J Am Chem Soc. 2024 Mar 13;146(10):6522-6529. doi: 10.1021/jacs.3c09694. Epub 2024 Feb 28.

DOI:10.1021/jacs.3c09694
PMID:38417010
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11162201/
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 型受体（PTH1R）在介导钙稳态和骨骼发育中发挥着关键作用，异常的 PTH1R 活性是多种人类疾病的基础。肽类 PTH1R 拮抗剂和反向激动剂具有治疗这些疾病的潜力，但它们较差的药代动力学和药效动力学削弱了它们在体内的疗效。在此，我们报告了使用骨架修饰策略来设计一种肽类 PTH1R 抑制剂，该抑制剂在体外和体内均表现出作为野生型 PTH1R 的拮抗剂和组成型激活的 PTH1R-H223R 突变体的反向激动剂的延长活性。该肽可能对未来开发改善 PTH1R 功能障碍的治疗药物具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/0040135c27bf/nihms-1994002-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/2133288d0d4e/nihms-1994002-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/9ffda41d03b2/nihms-1994002-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/227344f14743/nihms-1994002-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/cd3b385ff923/nihms-1994002-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/08abf8185f06/nihms-1994002-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/0040135c27bf/nihms-1994002-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/2133288d0d4e/nihms-1994002-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/9ffda41d03b2/nihms-1994002-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/227344f14743/nihms-1994002-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/cd3b385ff923/nihms-1994002-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/08abf8185f06/nihms-1994002-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37dd/11162201/0040135c27bf/nihms-1994002-f0006.jpg

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Acta Pharm Sin B. 2023 Apr;13(4):1648-1659. doi: 10.1016/j.apsb.2022.10.014. Epub 2022 Oct 21.
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