title: Angiotensin-(1-7) with thioether bridge: an angiotensin-converting enzyme-resistant, potent angiotensin-(1-7) analog.
abstract: The in vivo efficacy of many therapeutic peptides is hampered by their rapid proteolytic degradation. Cyclization of these therapeutic peptides is an excellent way to render them more resistant against breakdown. Here, we describe the enzymatic introduction of a thioether ring in angiotensin [Ang-(1-7)], a heptapeptide that plays a pivotal role in the renin-angiotensin system and possesses important therapeutic activities. The lactic acid bacterium Lactococcus lactis, equipped with the plasmid-based nisin modification machinery, was used to produce thioether-bridged Ang-(1-7). The resulting cyclized Ang-(1-7) is fully resistant against purified angiotensin-converting enzyme, has significantly increased stability in homogenates of different organs and in plasma derived from pig, and displays a strongly (34-fold) enhanced survival in Sprague-Dawley (SD) rats in vivo. With respect to functional activity, cyclized Ang-(1-7) induces relaxation of precontracted SD rat aorta rings in vitro. The magnitude of this effect is 2-fold larger than that obtained for natural Ang-(1-7). The Ang-(1-7) receptor antagonist D-Pro(7)-Ang-(1-7), which completely inhibits the activity of natural Ang-(1-7), also abolishes the vasodilation by cyclized Ang-(1-7), providing evidence that cyclized Ang-(1-7) also interacts with the Ang-(1-7) receptor. Taken together, applying a highly innovative enzymatic peptide stabilization method, we generated a stable Ang-(1-7) analog with strongly enhanced therapeutic potential.
authors.affiliation: BiOMaDe Technology Foundation, Groningen, The Netherlands.
authors.forename: Leon D
authors.initials: LD
authors.lastname: Kluskens
authors.forename: S Adriaan
authors.initials: SA
authors.lastname: Nelemans
authors.forename: Rick
authors.initials: R
authors.lastname: Rink
authors.forename: Louwe
authors.initials: L
authors.lastname: de Vries
authors.forename: Anita
authors.initials: A
authors.lastname: Meter-Arkema
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Anneke
authors.initials: A
authors.lastname: Kuipers
authors.forename: Gert N
authors.initials: GN
authors.lastname: Moll
authors.forename: Marijke
authors.initials: M
authors.lastname: Haas
mesh_terms: D000809:Angiotensins / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D004355:Drug Stability; D007262:Infusions, Intravenous; D007672:Kidney Cortex / Q000378:metabolism; D013294:Lactococcus lactis / Q000201:enzymology; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000032:analysis*; D013552:Swine
chemical_list: D000809:Angiotensins; D001426:Bacterial Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D013440:Sulfides; D007703:Peptidyl-Dipeptidase A