Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytes
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Pathogen Genomics Laboratory
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AbstractOne 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 PKAis 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.
CitationHaidar M, de Laté PL, Kennedy EJ, Langsley G (2017) Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytes. Bioorganic & Medicinal Chemistry. Available: http://dx.doi.org/10.1016/j.bmc.2017.08.056.
SponsorsMK and GL acknowledge support from a CRG4 grant [URF/1/2610-01-01] from the Office for Sponsored Research (OSR) in King Abdullah University of Science and Technology (KAUST). PLdL and GL acknowledge support from an ANR-11-LABX-0024 grant and GL core funding from INSERM and the CNRS. EJK acknowledges support by the National Institutes of Health (CA154600 and CA188439).
JournalBioorganic & Medicinal Chemistry
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