Effective treatment of experimental ragweed‐induced asthma with <scp>STAT</scp>‐6‐<scp>IP</scp>, a topically delivered cell‐penetrating peptide

Wang, Yifan; Li, Yunguo; Shan, Jichuan; Fixman, Elizabeth D.; McCusker, Christine

doi:10.1111/j.1365-2222.2011.03853.x

Cited by 31 publications

(40 citation statements)

References 23 publications

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“…This highlights the need for well-defined asthma models specifically suited for addressing disease mechanisms or for evaluating existing and novel therapies. Chronic sensitisation protocols have been reported to result in models of pronounced Th2-type disease [10,11,12,15], more mixed types of diseases [14,30,31], and even dexamethasone insensitive disease [32]. Our cat allergen-induced asthma model exhibits characteristics of Th17/neutrophilic asthma with increased neutrophil numbers in BAL and increased levels of IL-17a in lung tissue.…”

Section: Discussionmentioning

confidence: 93%

“…Recently, both improved chronic OVA protocols [10] and protocols with relevant inhaled allergens (e.g. dust mite, pollen and moulds [11,12,13,14]) have been developed. Chronic asthma models have been employed in a number of studies of disease and treatment mechanisms [12,14,15,16,17,18], but there is still a need for improved models of allergy and asthma induced by allergens relevant for human disease.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Grundström

Saarne

Kemi³

et al. 2014

Int Arch Allergy Immunol

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Background: Allergic asthma is a chronic inflammatory airway disease caused by exposure to airborne allergens. In order to develop novel therapies for allergic asthma, models that are relevant to human disease are needed. Methods: Female BALB/c mice were presensitised subcutaneously with alum-adsorbed recombinant cat allergen Fel d 1, followed by intranasal challenges with cat dander extract spiked with recombinant Fel d 1 for 7 weeks. For reference, mice were presensitised and challenged with ovalbumin following the same protocol. Airway hyperresponsiveness, serum antibodies, airway inflammation and cell infiltration, and cytokines in lung tissue and bronchoalveolar lavage were measured. Results: Mice presensitised with recombinant Fel d 1 and challenged with cat dander extract or presensitised and challenged with ovalbumin showed airway hyperresponsiveness in response to metacholine. Mice of the cat allergen model showed influx of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage, combined with increased levels of IL-17a and increased IL-4 mRNA expression in lung tissue. In contrast, mice sensitised and challenged with ovalbumin showed a predominant influx of eosinophils in bronchoalveolar lavage and had an increased expression of IL-5 in lung tissue. Both protocols induced features of lung tissue remodelling and allergen-specific antibody responses. Conclusions: The presented mouse model for cat allergen-induced asthma exhibits hallmarks of chronic allergic asthma, like airway hyperresponsiveness, a mixed neutrophilic/eosinophilic infiltration in bronchoalveolar lavage, expression of IL-17a and signs of remodelling in lung tissue. The model will provide a relevant platform for the development of novel treatment strategies.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Grundström

Saarne

Kemi³

et al. 2014

Int Arch Allergy Immunol

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“…A recent report also showed that a chimeric STAT6-inhibitory peptide, STAT6-IP, blocked the T H 2 cytokines IL-4 and IL-13, and chemokine production. The intranasal delivery of STAT6-IP inhibited the ovalbumin-induced lung inflammation, mucus production and eosinophil accumulation in the lungs 152 , while its topical application in an in vivo model of chronic ragweed-induced asthma suppressed the production of T H 2 cytokines 153 .…”

Section: Inhibitors Of Stat6mentioning

confidence: 99%

Therapeutic modulators of STAT signalling for human diseases

Miklóssy

Hilliard

Turkson

2013

Nat Rev Drug Discov

354

334

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The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

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“…1,2 These include small molecules without described inhibitory mechanisms, 7–12 non-SH2 domain directed dimerization inhibitors, 13 JAK inhibitors, 14,15 siRNA, 6 decoy oligonucleotides, 16 phosphopeptides targeting the SH2 domain of STAT6, 17–19 antibodies targeting IL-13, 20 and antibodies targeting IL-4Rα. 20–22 Our approach is to target the SH2 domain of STAT6 with small molecule peptidomimetics to block recruitment to IL-4Rα, thereby preventing subsequent phosphorylation of Tyr641 by JAKs, dimerization, translocation to the nucleus, and transcription of genes, leading to airway inflammation.…”

Section: Introductionmentioning

confidence: 99%

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

Mandal¹,

Morlacchi

Knight³

et al. 2015

J. Med. Chem.

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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.

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Effective treatment of experimental ragweed‐induced asthma with STAT‐6‐IP, a topically delivered cell‐penetrating peptide

Cited by 31 publications

References 23 publications

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Therapeutic modulators of STAT signalling for human diseases

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

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