A proopiomelanocortin‐derived peptide sequence enhances plasma stability of peptide drugs,FEBS Letters

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A proopiomelanocortin‐derived peptide sequence enhances plasma stability of peptide drugs
FEBS Letters ( IF 3.0 ) Pub Date : 2020-06-27 , DOI: 10.1002/1873-3468.13855
Karin Löw _{1,

2} , Alexandre Roulin ₂ , Stefan Kunz ₁

Affiliation

Bioactive peptide drugs hold promise for therapeutic application due to their high potency and selectivity but display short plasma half‐life. Examination of selected naturally occurring peptide hormones derived from proteolytic cleavage of the proopiomelanocortin (POMC) precursor lead to the identification of significant plasma‐stabilizing properties of a 12‐amino acid serine‐rich orphan sequence NSSSSGSSGAGQ in human γ3‐melanocyte‐stimulating hormone (MSH) that is homologous to previously discovered NSnGGH (n = 4–24) sequences in owls. Notably, transfer of this sequence to des‐acetyl‐α‐MSH and the therapeutically relevant peptide hormones neurotensin and glucagon‐like peptide‐1 likewise enhance their plasma stability without affecting receptor signaling. The stabilizing effect of the sequence module is independent of plasma components, suggesting a direct effect in cis. This natural sequence module may provide a possible strategy to enhance plasma stability, complementing existing methods of chemical modification.

中文翻译：

阿黑皮素原衍生肽序列增强肽药物的血浆稳定性

生物活性肽药物因其高效力和选择性而具有治疗应用前景，但血浆半衰期较短。对源自阿黑皮素原 (POMC) 前体的蛋白水解裂解的选定天然肽激素的检查导致鉴定了人 γ3-黑素细胞刺激素 (MSH) 中富含 12 个氨基酸的丝氨酸孤儿序列 NSSSSGSSGAGQ 的显着血浆稳定特性) 与之前在猫头鹰中发现的 NSnGGH (n = 4-24) 序列同源。值得注意的是，将该序列转移到去乙酰基-α-MSH 和治疗相关的肽激素神经降压素和胰高血糖素样肽-1 同样增强了它们的血浆稳定性而不影响受体信号传导。序列模块的稳定作用与等离子体成分无关，表明顺式的直接作用。这种自然序列模块可以提供一种可能的策略来增强血浆稳定性，补充现有的化学修饰方法。

更新日期：2020-06-27

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