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Open AccessArticle

A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A

Department of Biochemistry, Institute for Biology, University of Kassel, Heinrich-Plett-Str. 40, 34132 Kassel, Germany
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 240 W. Green St, Athens, GA 30602, USA
Authors to whom correspondence should be addressed.
These Authors contributed equally to this work.
Current address: Boehringer Ingelheim Pharma GmbH & Co. KG, Analytical Developments Biologicals, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.
Academic Editors: Henry Mosberg, Tomi Sawyer and Carrie Haskell-Luevano
Molecules 2019, 24(8), 1567;
Received: 30 March 2019 / Revised: 17 April 2019 / Accepted: 19 April 2019 / Published: 20 April 2019
Kinases regulate multiple and diverse signaling pathways and misregulation is implicated in a multitude of diseases. Although significant efforts have been put forth to develop kinase-specific inhibitors, specificity remains a challenge. As an alternative to catalytic inhibition, allosteric inhibitors can target areas on the surface of an enzyme, thereby providing additional target diversity. Using cAMP-dependent protein kinase A (PKA) as a model system, we sought to develop a hydrocarbon-stapled peptide targeting the pseudosubstrate domain of the kinase. A library of peptides was designed from a Protein Kinase Inhibitor (PKI), a naturally encoded protein that serves as a pseudosubstrate inhibitor for PKA. The binding properties of these peptide analogs were characterized by fluorescence polarization and surface plasmon resonance, and two compounds were identified with KD values in the 500–600 pM range. In kinase activity assays, both compounds demonstrated inhibition with 25–35 nM IC50 values. They were also found to permeate cells and localize within the cytoplasm and inhibited PKA activity within the cellular environment. To the best of our knowledge, these stapled peptide inhibitors represent some of the highest affinity binders reported to date for hydrocarbon stapled peptides. View Full-Text
Keywords: PKA; stapled peptide; PKI; pseudosubstrate; kinase inhibitor; IP20 PKA; stapled peptide; PKI; pseudosubstrate; kinase inhibitor; IP20
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Manschwetus, J.T.; Bendzunas, G.N.; Limaye, A.J.; Knape, M.J.; Herberg, F.W.; Kennedy, E.J. A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A. Molecules 2019, 24, 1567.

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