Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity.
Signal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure-affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Rα bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13-stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6.
Pijus K
PK
Mandal
Pietro
P
Morlacchi
J Morgan
JM
Knight
Todd M
TM
Link
Gilbert R
GR
Lee
Roza
R
Nurieva
Divyendu
D
Singh
The Department of Computer Science, Rice University , Houston, Texas 77251, United States.
Ankur
A
Dhanik
The Department of Computer Science, Rice University , Houston, Texas 77251, United States.
Lydia
L
Kavraki
Departments of Medicine and Pathology & Immunology, The Baylor College of Medicine , Houston, Texas 77030, United States.
David B
DB
Corry
John E
JE
Ladbury
John S
JS
McMurray
D000818:Animals; D001249:Asthma / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018793:Interleukin-13 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010748:Phosphopeptides / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs; D051381:Rats; D016185:Receptors, Interleukin-3 / Q000187:drug effects; D019948:Receptors, Interleukin-4 / Q000187:drug effects; D050800:STAT6 Transcription Factor / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D018909:src Homology Domains / Q000187:drug effects*
D018793:Interleukin-13; D010748:Phosphopeptides; D011355:Prodrugs; D016185:Receptors, Interleukin-3; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D014443:Tyrosine; D010744:Phosphoric Monoester Hydrolases