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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Angiotensin-(1-7) with thioether bridge: An angiotensin- converting enzyme-resistant, potent angiotensin-(1-7) analog
Journal of Pharmacology and Experimental Therapeutics, Volume 328, No. 3, Year 2009
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Description
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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.
Authors & Co-Authors
Kluskens, Leon D.
Netherlands, Groningen
Rijksuniversiteit Groningen
Portugal, Braga
Universidade do Minho
Ad Nelemans, S.
Netherlands, Groningen
Rijksuniversiteit Groningen
Rink, Rick
Netherlands, Groningen
Rijksuniversiteit Groningen
de Vries, Louwe
Netherlands, Groningen
Rijksuniversiteit Groningen
Meter-Arkema, Anita H.
Netherlands, Groningen
Rijksuniversiteit Groningen
Netherlands, Groningen
Universitair Medisch Centrum Groningen
Wang, Yong
Germany, Berlin
Charité – Universitätsmedizin Berlin
United Kingdom, Hull
Hull York Medical School
Walther, Thomas
Germany, Berlin
Charité – Universitätsmedizin Berlin
United Kingdom, Hull
Hull York Medical School
Kuipers, Anneke
Netherlands, Groningen
Rijksuniversiteit Groningen
Moll, Gert N.
Netherlands, Groningen
Rijksuniversiteit Groningen
Netherlands, Groningen
Bio ma de
Haas, Marijke
Netherlands, Groningen
Rijksuniversiteit Groningen
Nigeria, Ilorin
University of Ilorin
Statistics
Citations: 135
Authors: 10
Affiliations: 7
Identifiers
Doi:
10.1124/jpet.108.146431
ISSN:
00223565
e-ISSN:
15210103