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Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-24 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00876 Ross W. Cheloha 1 , Bingming Chen 2 , Niyanta N. Kumar 2 , Tomoyuki Watanabe 3 , Robert G. Thorne 2, 4, 5, 6 , Lingjun Li 1, 2 , Thomas J. Gardella 3 , Samuel H. Gellman 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-10-24 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00876 Ross W. Cheloha 1 , Bingming Chen 2 , Niyanta N. Kumar 2 , Tomoyuki Watanabe 3 , Robert G. Thorne 2, 4, 5, 6 , Lingjun Li 1, 2 , Thomas J. Gardella 3 , Samuel H. Gellman 1
Affiliation
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The parathyroid hormone receptor 1 (PTHR1) is a member of the B-family of GPCRs; these receptors are activated by long polypeptide hormones and constitute targets of drug development efforts. Parathyroid hormone (PTH, 84 residues) and PTH-related protein (PTHrP, 141 residues) are natural agonists of PTHR1, and an N-terminal fragment of PTH, PTH(1–34), is used clinically to treat osteoporosis. Conventional peptides in the 20–40-mer length range are rapidly degraded by proteases, which may limit their biomedical utility. We have used the PTHR1–ligand system to explore the impact of broadly distributed replacement of α-amino acid residues with β-amino acid residues on susceptibility to proteolysis and agonist activity. This effort led us to identify new PTHR1 agonists that contain α → β replacements throughout their sequences, manifest potent agonist activity in cellular assays, and display remarkable resistance to proteolysis, in cases remaining active after extended exposure to simulated gastric fluid. The strategy we have employed suggests a path toward identifying protease-resistant agonists of other B-family GPCRs.
中文翻译：
β残基分布广泛的甲状旁腺激素受体的强力，耐蛋白酶激动剂的开发。
甲状旁腺激素受体1（PTHR1）是GPCR的B族成员；这些受体被长多肽激素激活，并构成药物开发努力的目标。甲状旁腺激素（PTH，84个残基）和PTH相关蛋白（PTHrP，141个残基）是PTHR1的天然激动剂，PTH的N端片段PTH（1-34）在临床上用于治疗骨质疏松症。长度在20至40个单体之间的常规肽会被蛋白酶迅速降解，这可能会限制其生物医学用途。我们已经使用PTHR1-配体系统来探索用β-氨基酸残基广泛分布替换α-氨基酸残基对蛋白水解和激动剂活性的影响。这项工作使我们确定了新的PTHR1激动剂，这些激动剂在其整个序列中都包含α→β替代，在长时间暴露于模拟胃液后仍保持活性的情况下，在细胞试验中表现出强大的激动剂活性，并表现出对蛋白水解的显着抵抗力。我们采用的策略为鉴定其他B族GPCR的蛋白酶抗性激动剂提供了一条途径。
更新日期：2017-10-24
中文翻译：
β残基分布广泛的甲状旁腺激素受体的强力，耐蛋白酶激动剂的开发。
甲状旁腺激素受体1（PTHR1）是GPCR的B族成员；这些受体被长多肽激素激活，并构成药物开发努力的目标。甲状旁腺激素（PTH，84个残基）和PTH相关蛋白（PTHrP，141个残基）是PTHR1的天然激动剂，PTH的N端片段PTH（1-34）在临床上用于治疗骨质疏松症。长度在20至40个单体之间的常规肽会被蛋白酶迅速降解，这可能会限制其生物医学用途。我们已经使用PTHR1-配体系统来探索用β-氨基酸残基广泛分布替换α-氨基酸残基对蛋白水解和激动剂活性的影响。这项工作使我们确定了新的PTHR1激动剂，这些激动剂在其整个序列中都包含α→β替代，在长时间暴露于模拟胃液后仍保持活性的情况下，在细胞试验中表现出强大的激动剂活性，并表现出对蛋白水解的显着抵抗力。我们采用的策略为鉴定其他B族GPCR的蛋白酶抗性激动剂提供了一条途径。
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