2. Academic Validation
  3. Metabolically stable apelin-analogues, incorporating cyclohexylalanine and homoarginine, as potent apelin receptor activators

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

  • RSC Med Chem. 2021 Jul 8;12(8):1402-1413. 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
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Alberta 11227 Saskatchewan Drive NW Edmonton Alberta T6G 2G2 Canada john.vederas@ualberta.ca.
  • 2 Department of Physiology, University of Alberta 8440-112 Street NW Edmonton Alberta T6G 2B7 Canada.
  • 3 Mazankowski Alberta Heart Institute, University of Alberta 8440-112 St. NW Edmonton Alberta T6G 2B7 Canada.
  • 4 Department of Medicine, University of Alberta 8440-112 Street NW Edmonton Alberta T6G 2B7 Canada.
  • 5 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM 1050 Paris F-75005 France.
  • 6 Center for Interdisciplinary Research in Biology (CIRB), College de France Paris F-75005 France.
  • 7 CNRS UMR 7241 Paris F-75005 France.
PMID: 34458742 DOI: 10.1039/d1md00120e
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.

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