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

Handle URI:
http://hdl.handle.net/10754/625451
Title:
Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytes
Authors:
Haidar, Malak; de Laté, Perle Latré; Kennedy, Eileen J.; Langsley, Gordon
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 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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Pathogen Genomics Laboratory
Citation:
Haidar 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.
Publisher:
Elsevier BV
Journal:
Bioorganic & Medicinal Chemistry
Issue Date:
8-Sep-2017
DOI:
10.1016/j.bmc.2017.08.056
Type:
Article
ISSN:
0968-0896
Sponsors:
MK 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).
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0968089617313172
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorHaidar, Malaken
dc.contributor.authorde Laté, Perle Latréen
dc.contributor.authorKennedy, Eileen J.en
dc.contributor.authorLangsley, Gordonen
dc.date.accessioned2017-09-14T06:03:52Z-
dc.date.available2017-09-14T06:03:52Z-
dc.date.issued2017-09-08en
dc.identifier.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.en
dc.identifier.issn0968-0896en
dc.identifier.doi10.1016/j.bmc.2017.08.056en
dc.identifier.urihttp://hdl.handle.net/10754/625451-
dc.description.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.en
dc.description.sponsorshipMK 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).en
dc.publisherElsevier BVen
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0968089617313172en
dc.rightsNOTICE: this is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic & Medicinal Chemistry, [, , (2017-09-08)] DOI: 10.1016/j.bmc.2017.08.056 . © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectCell penetrating peptidesen
dc.subjectTheileriaen
dc.subjectPKA, BAD, Grb-2en
dc.subjectJNKen
dc.titleCell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria -transformed leukocytesen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentPathogen Genomics Laboratoryen
dc.identifier.journalBioorganic & Medicinal Chemistryen
dc.eprint.versionPost-printen
dc.contributor.institutionLaboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médecine, Université Paris Descartes - Sorbonne Paris Cité, 75014, Franceen
dc.contributor.institutionInserm U1016, Cnrs UMR8104, Cochin Institute, Paris 75014, Franceen
dc.contributor.institutionDepartment of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, United Statesen
kaust.authorHaidar, Malaken
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