2. Academic Validation
  3. Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents

Plasma kallikrein cleaves and inactivates apelin-17: Palmitoyl- and PEG-extended apelin-17 analogs as metabolically stable blood pressure-lowering agents

  • Eur J Med Chem. 2019 Mar 15:166:119-124. doi: 10.1016/j.ejmech.2019.01.040.
Conrad Fischer 1,  Tess Lamer 1,  Wang Wang 2,  Shaun M K McKinnie 1,  Xavier Iturrioz 3,  Catherine Llorens-Cortes 3,  Gavin Y Oudit 2,  John C Vederas 4
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada.
  • 2 Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440-112 St. NW, Edmonton, Alberta, T6G 2B7, Canada.
  • 3 Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, INSERM, U1050, Paris, F-75005, France; Center for Interdisciplinary Research in Biology (CIRB), College de France, Paris, F-75005, France; CNRS, UMR 7241, Paris, F-75005, France.
  • 4 Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive NW, Edmonton, Alberta, T6G 2G2, Canada. Electronic address: John.Vederas@ualberta.ca.
PMID: 30690406 DOI: 10.1016/j.ejmech.2019.01.040
Abstract

Apelins are human peptide Hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma Kallikrein (KLKB1) as a protease that cleaves the first three N-terminal Amino acids (KFR) of apelin-17. The cleavage kinetics are similar to Neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated apelin-17(A2) is a highly protease resistant analog, with excellent apelin receptor activation and pronounced blood pressure lowering effect.

Keywords

Apelin; Cardiovascular disease; Peptide mimetics; Plasma kallikrein.

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