Thioamide Substitution Selectively Modulates Proteolysis and Receptor Activity of Therapeutic Peptide Hormones.
Thioamide Substitution Selectively Modulates Proteolysis and Receptor Activity of Therapeutic Peptide Hormones.
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硫酰胺取代选择性调节治疗性肽激素的蛋白水解和受体活性。
DOI：
10.1021/jacs.7b08417
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发表时间：
2017-11-22
影响因子：
15
通讯作者：
Petersson EJ
中科院分区：
文献类型：
--
作者：
Chen X;Mietlicki-Baase EG;Barrett TM;McGrath LE;Koch-Laskowski K;Ferrie JJ;Hayes MR;Petersson EJ
肽激素作为注射治疗药物和显像剂很有吸引力，但它们通常需要通过诱变和/或化学合成进行广泛的修饰，以防止体内快速降解。另外，肽主链硫胺化的单原子O-to-S修饰有可能选择性地干扰与蛋白酶的相互作用，同时保留与其他蛋白质（如靶受体）的相互作用。在这里，我们使用经过验证的糖尿病治疗，胰高血糖素样肽-1 （GLP-1）和临床研究的目标，胃抑制多肽（GIP），作为原理证明肽来证明硫酰胺替代的价值。在GLP-1和GIP中，靠近可剪切键的单个硫酰胺使这些肽比相应的氧化肽更容易被二肽基肽酶4（其体内稳定性的主要调节因子）切割，稳定性高达750倍。在环AMP激活试验中，这些稳定的类似物与它们的亲本肽几乎具有相同的效力，但GLP-1硫肽的β-抑制素效力要低得多，这使它们成为具有改变信号偏倚的新型激动剂。初步试验表明，硫酰胺GLP-1类似物在大鼠体内具有生物活性，其体内血糖控制效力超过天然GLP-1。综上所述，这些实验证明了硫酰胺调节特定蛋白质相互作用的潜力，以增加蛋白质水解稳定性或调节不同信号通路的激活。
Peptide hormones are attractive as injectable therapeutics and imaging agents, but they often require extensive modification by mutagenesis and/or chemical synthesis to prevent rapid in vivo degradation. Alternatively, the single atom, O-to-S modification of peptide backbone thioamidation has the potential to selectively perturb interactions with proteases while preserving interactions with other proteins, such as target receptors. Here, we use the validated diabetes therapeutic, glucagon-like peptide-1 (GLP-1), and the target of clinical investigation, gastric inhibitory polypeptide (GIP), as proof-of-principle peptides to demonstrate the value of thioamide substitution. In GLP-1 and GIP, a single thioamide near the scissile bond renders these peptides up to 750-fold more stable than the corresponding oxopeptides toward cleavage by dipeptidyl peptidase 4, the principle regulator of their in vivo stability. These stabilized analogs are nearly equipotent with their parent peptide in cyclic AMP activation assays, but the GLP-1 thiopeptides have much lower β-arrestin potency, making them novel agonists with altered signaling bias. Initial tests show that a thioamide GLP-1 analog is biologically active in rats, with an in vivo potency for glycemic control surpassing that of native GLP-1. Taken together, these experiments demonstrate the potential for thioamides to modulate specific protein interactions to increase proteolytic stability or tune activation of different signaling pathways.
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影响因子：
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