Institute of Microbiology, University Hospital Center and University of Lausanne, Switzerland.
Department of Ecology and Evolution, University of Lausanne, Switzerland.
FEBS Lett. 2020 Sep;594(17):2840-2866. doi: 10.1002/1873-3468.13855. Epub 2020 Jun 27.
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 NS GGH (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.
生物活性肽药物由于其高效性和选择性而有希望应用于治疗，但它们的血浆半衰期较短。对来源于蛋白前体酶切的特定天然存在的肽激素的研究，导致了在人类 γ3-促黑色素细胞激素（MSH）中发现了 12 个氨基酸的丝氨酸丰富的孤儿序列 NSSSSGSSGAGQ 具有显著的稳定血浆的特性，该序列与先前在猫头鹰中发现的 NS GGH（n=4-24）序列同源。值得注意的是，将该序列转移到去乙酰-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 上同样可以增强它们的血浆稳定性，而不影响受体信号转导。序列模块的稳定作用不依赖于血浆成分，提示其在顺式中具有直接作用。这个天然序列模块可能为增强血浆稳定性提供了一种可行的策略，补充了现有的化学修饰方法。
