Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators,RSC Medicinal Chemistry

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Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-07-08 , DOI: 10.1039/d1md00120e
Kleinberg X Fernandez ₁ , Conrad Fischer ₁ , Jennie Vu ₂ , Mahmoud Gheblawi _{2,

3} , Wang Wang _{2,

4} , Samantha Gottschalk ₁ , Xavier Iturrioz _{5,

6,

7} , Catherine Llorens-Cortés _{5,

6,

7} , Gavin Y Oudit _{2,

3} , John C Vederas ₁

Affiliation

High blood pressure and consequential cardiovascular diseases are among the top causes of death worldwide. The apelinergic (APJ) system has emerged as a promising target for the treatment of cardiovascular issues, especially prevention of ischemia reperfusion (IR) injury after a heart attack or stroke. However, rapid degradation of the endogenous apelin peptides in vivo limits their use as therapeutic agents. Here, we study the effects of simple homologue substitutions, i.e. incorporation of non-canonical amino acids L-cyclohexylalanine (L-Cha) and L-homoarginine (L-hArg), on the proteolytic stability of pyr-1-apelin-13 and apelin-17 analogues. The modified 13-mers display up to 40 times longer plasma half-life than native apelin-13 and in preliminary in vivo assay show moderate blood pressure-lowering effects. The corresponding apelin-17 analogues show pronounced blood pressure-lowering effects and up to a 340-fold increase in plasma half-life compared to the native apelin-17 isoforms, suggesting their potential use in the design of metabolically stable apelin analogues to prevent IR injury.

中文翻译：

代谢稳定的 apelin 类似物，包含环己基丙氨酸和高精氨酸，作为有效的 apelin 受体激活剂

高血压和随之而来的心血管疾病是全球死亡的主要原因之一。apelinergic (APJ) 系统已成为治疗心血管问题的有希望的目标，特别是预防心脏病发作或中风后的缺血再灌注 (IR) 损伤。然而，内源性apelin肽在体内的快速降解限制了它们作为治疗剂的用途。在这里，我们研究了简单的同源物取代的影响，即非规范氨基酸L-环己基丙氨酸 ( L -Cha) 和L-高精氨酸 ( L-hArg)，关于 pyr-1-apelin-13 和 apelin-17 类似物的蛋白水解稳定性。修饰的 13-mers 的血浆半衰期比天然 apelin-13 长 40 倍，初步体内试验显示出适度的降血压作用。与天然 apelin-17 同种型相比，相应的 apelin-17 类似物显示出明显的降血压作用，血浆半衰期增加高达 340 倍，表明它们在设计代谢稳定的 apelin 类似物以预防 IR 中的潜在用途受伤。

更新日期：2021-07-09

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