2. Academic Validation
  3. A nonnatural peptide targeting the A-kinase anchoring function of PI3Kγ for therapeutic cAMP modulation in pulmonary cells

A nonnatural peptide targeting the A-kinase anchoring function of PI3Kγ for therapeutic cAMP modulation in pulmonary cells

  • J Biol Chem. 2024 Oct 10;300(11):107873. doi: 10.1016/j.jbc.2024.107873.
Angela Della Sala 1,  Laura Tasca 2,  Cosmin Butnarasu 1,  Valentina Sala 2,  Giulia Prono 1,  Alessandra Murabito 1,  Olga Valentina Garbero 1,  Enrico Millo 3,  Leonardo Terranova 4,  Francesco Blasi 5,  Andrea Gramegna 5,  Stefano Aliberti 6,  Alberto Massarotti 7,  Sonja Visentin 1,  Emilio Hirsch 2,  Alessandra Ghigo 8
Affiliations

Affiliations

  • 1 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, Torino, Italy.
  • 2 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, Torino, Italy; Kither Biotech Srl, Torino, Italy.
  • 3 Section of Biochemistry, Department of Experimental Medicine, University of Genova, Genova, Italy.
  • 4 Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Microbiology and Virology Specialization School, University of Pavia, Pavia, Italy.
  • 5 Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
  • 6 Respiratory Unit, IRCCS Humanitas Research Hospital, Humanitas University, Milan, Italy.
  • 7 Department of Pharmaceutical Science, University of Piemonte Orientale, Novara, Italy.
  • 8 Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Torino, Torino, Italy; Kither Biotech Srl, Torino, Italy. Electronic address: alessandra.ghigo@unito.it.
PMID: 39393573 DOI: 10.1016/j.jbc.2024.107873
Abstract

A-kinase anchoring proteins (AKAPs) are key orchestrators of cAMP signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of phosphoinositide 3-kinase γ (PI3Kγ) improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport, and antiinflammatory responses. Here, we report the generation of a nonnatural peptide, D-retroinverso (DRI)-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to Protease degradation and high permeability to the pulmonary mucus barrier. DRI-Pep #20 triggered cAMP elevation both in vivo in the airway tract of mice upon intratracheal administration, and in vitro in bronchial epithelial cells of cystic fibrosis (CF) patients. In CF cells, DRI-Pep #20 rescued the defective function of the cAMP-operated channel cystic fibrosis transmembrane conductance regulator, by boosting the efficacy of approved cystic fibrosis transmembrane conductance regulator modulators. Overall, this study unveils DRI-Pep #20 as a potent PI3Kγ/PKA disruptor for achieving therapeutic cAMP elevation in chronic respiratory disorders.

Keywords

AKAP; PI3Kγ; PKA; cAMP; peptide; respiratory diseases.

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