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

Kleinberg X. Fernandez; Conrad Fischer; Jennie Vu; Mahmoud Gheblawi; Wang Wang; Samantha Gottschalk; Xavier Iturrioz; Catherine Llorens-Cortés; Gavin Y. Oudit; John C. Vederas

doi:10.1039/D1MD00120E

Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators†

Kleinberg X. Fernandez,

^a Conrad Fischer,

‡^a Jennie Vu,^b Mahmoud Gheblawi,^bc Wang Wang,^bd Samantha Gottschalk,

^a Xavier Iturrioz,§^efg Catherine Llorens-Cortés,^efg Gavin Y. Oudit^bc and John C. Vederas

*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, Canada
E-mail: john.vederas@ualberta.ca

^b Department of Physiology, University of Alberta, 8440-112 Street NW, Edmonton, Alberta T6G 2B7, Canada

^c Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, Canada

^d Department of Medicine, University of Alberta, 8440-112 Street NW, Edmonton, Alberta T6G 2B7, Canada

^e Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, 1050, Paris, France

^f Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, France

^g CNRS, UMR 7241, Paris, France

Abstract

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.

RSC Medicinal Chemistry

Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators†

Abstract

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

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