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Bioorg Med Chem. 2018 Mar 15;26(6):1127-1134. doi: 10.1016/j.bmc.2017.08.056. Epub 2017 Sep 7.

Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria-transformed leukocytes.

Author information

1
Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris 75014, France; Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité, 75014, France; Pathogen Genomics Laboratory, Biological and Environmental Sciences and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
2
Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris 75014, France; Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité, 75014, France.
3
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, United States.
4
Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris 75014, France; Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité, 75014, France. Electronic address: gordon.langsley@inserm.fr.

Abstract

One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets. Theileria-transformed leukocytes display high PKA activity, but PKA is an enzyme that plays key roles in multiple cellular processes; consequently genetic ablation of kinase activity gives rise to a myriad of confounding phenotypes. By contrast, ablation of a specific kinase-substrate interaction has the potential to give more refined information and we illustrate this here by describing how surgically ablating PKA interactions with BAD gives precise information on the type of glycolysis performed by Theileria-transformed leukocytes. In addition, we provide two other examples of how ablating specific protein-protein interactions in Theileria-infected leukocytes leads to precise phenotypes and argue that constrained penetrating peptides have great therapeutic potential to combat infectious diseases in general.

KEYWORDS:

Cell penetrating peptides; JNK; PKA, BAD, Grb-2; Theileria

PMID:
28917447
PMCID:
PMC5842112
[Available on 2019-03-15]
DOI:
10.1016/j.bmc.2017.08.056
[Indexed for MEDLINE]
Free PMC Article

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