Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1–34)-NH₂ that contained a single β-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1–34)-NH₂ itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The β-scan series allowed us to identify two homologs, each containing two α→β replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both β²- and β³-residues, which differ in terms of side-chain location.

人甲状旁腺激素（PTH）及其N端片段会激活两个受体hPTHR1和hPTHR2，它们具有约51％的序列相似性。包含PTH的前34个残基的肽在两个受体上均具有完全活性，可用于治疗骨质疏松症。我们已经使用该系统来探索这样的假设，即混杂的肽激动剂的骨架修饰可以提供新型的受体选择性激动剂。我们通过准备一组PTH（1-34）-NH ₂变异体来检验该假设，该变异体在前八个位置的每个位置均包含单个β-氨基酸残基置换。这些同系物，相对于PTH（1-34）-NH ₂，每个都含有一个额外的主链亚甲基单元本身，在基于细胞的PTHR1或PTHR2激活检测中显示出广泛的潜能。通过β扫描序列，我们可以鉴定出两个同源物，每个同源物都具有两个α→β替代物，它们具有很高的选择性，一个对PTHR1，另一个对PTHR2。这些研究结果表明肽的该主链修饰可提供用于实现多肽调制受体中激活选择性的一般策略，并且成功需要考虑两者的β ² -和β ³ -残基，其在侧链位置方面不同。