We have reported previously the design of a RIAD (RI-anchoring disruptor) peptide that specifically displaces PKA (protein kinase A) type I from the AKAP (A-kinase-anchoring protein) ezrin, which is present in the immunological synapse of T-cells. This increases immune reactivity by reducing the threshold for activation and may prove a feasible approach for improving immune function in patients with cAMP-mediated T-cell dysfunction. However, the use of RIAD in biological systems is restricted by its susceptibility to enzymatic cleavage and, consequently, its short half-life in presence of the ubiquitous serum peptidases. In the present study, carefully selected non-natural amino acids were employed in the design of RIAD analogues with improved stability. The resulting peptidomimetics demonstrated up to 50-fold increased half-lives in serum compared with RIAD, while maintaining similar or improved specificity and potency with respect to disruption of PKA type I–AKAP interactions.
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Research Article|
October 23 2009
Design of proteolytically stable RI-anchoring disruptor peptidomimetics for in vivo studies of anchored type I protein kinase A-mediated signalling
Eirik A. Torheim;
Eirik A. Torheim
1Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0317 Oslo, Norway
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Elisabeth Jarnæss;
Elisabeth Jarnæss
1Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0317 Oslo, Norway
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Birgitte Lygren;
Birgitte Lygren
1Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0317 Oslo, Norway
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Kjetil Taskén
Kjetil Taskén
1
1Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, N-0317 Oslo, Norway
1To whom correspondence should be addressed (email kjetil.tasken@biotek.uio.no).
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Publisher: Portland Press Ltd
Received:
June 22 2009
Revision Received:
August 17 2009
Accepted:
August 28 2009
Accepted Manuscript online:
August 28 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 424 (1): 69–78.
Article history
Received:
June 22 2009
Revision Received:
August 17 2009
Accepted:
August 28 2009
Accepted Manuscript online:
August 28 2009
Citation
Eirik A. Torheim, Elisabeth Jarnæss, Birgitte Lygren, Kjetil Taskén; Design of proteolytically stable RI-anchoring disruptor peptidomimetics for in vivo studies of anchored type I protein kinase A-mediated signalling. Biochem J 15 November 2009; 424 (1): 69–78. doi: https://doi.org/10.1042/BJ20090933
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