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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleCARDIOVASCULAR

Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog

Leon D. Kluskens, S. Adriaan Nelemans, Rick Rink, Louwe de Vries, Anita Meter-Arkema, Yong Wang, Thomas Walther, Anneke Kuipers, Gert N. Moll and Marijke Haas
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 849-854; DOI: https://doi.org/10.1124/jpet.108.146431
Leon D. Kluskens
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S. Adriaan Nelemans
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Rick Rink
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Louwe de Vries
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Anita Meter-Arkema
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Yong Wang
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Thomas Walther
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Anneke Kuipers
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Gert N. Moll
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Marijke Haas
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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-Pro7-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.

Footnotes

  • This work was supported by the Dutch Technology Foundation STW (Project 06927).

  • doi:10.1124/jpet.108.146431.

  • ABBREVIATIONS: Ang, angiotensin; RAS, renin-angiotensin system; ACE, angiotensin-converting enzyme; cAng-(1-7), 4-7 thioether-bridged angiotensin-(1-7); SD, Sprague-Dawley; PE, phenylephrine; A-779, d-Ala7-Ang-(1-7); AVE 0991, 5-formyl-4-methoxy-2-phenyl1-[[4-[2-ethylami-nocarbonylsulfonamido)-5-isobutyl-3-thienyl]-phenyl]-methyl]-imidazole.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Centro de Engenharia Biológica, Universidade do Minho, Braga, Portugal.

  • ↵2 Current affiliation: Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

  • ↵3 Current affiliation: Centre for Biomedical Research, Hull York Medical School, University of Hull, Hull, United Kingdom.

  • ↵4 Current affiliation: Department of Pharmacology and Therapy, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.

    • Received September 21, 2008.
    • Accepted November 26, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
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Research ArticleCARDIOVASCULAR

Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog

Leon D. Kluskens, S. Adriaan Nelemans, Rick Rink, Louwe de Vries, Anita Meter-Arkema, Yong Wang, Thomas Walther, Anneke Kuipers, Gert N. Moll and Marijke Haas
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 849-854; DOI: https://doi.org/10.1124/jpet.108.146431

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Research ArticleCARDIOVASCULAR

Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog

Leon D. Kluskens, S. Adriaan Nelemans, Rick Rink, Louwe de Vries, Anita Meter-Arkema, Yong Wang, Thomas Walther, Anneke Kuipers, Gert N. Moll and Marijke Haas
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 849-854; DOI: https://doi.org/10.1124/jpet.108.146431
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