Grozdanovic, Milica and Laffey, Kimberly G and Abdelkarim, Hazem and Hitchinson, Ben and Harijith, Anantha and Moon, Hyung-Geon and Park, Gye Young and Rousslang, Lee K. and Masterson, Joanne C. and Furuta, Glenn T. and Tarasova, Nadya I. and Gaponenko, Vadim and Ackerman, Steven J. (2019) Novel Peptide Nanoparticle Biased Antagonist of CCR3 Blocks Eosinophil Recruitment and Airway Hyperresponsiveness. Journal of Allergy and Clinical Immunology, 143 (2). pp. 669-680. ISSN 0091-6749

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Abstract

Background—Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason may be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance. Objective—We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G-protein signaling, but enable or promote receptor internalization. Methods—Self-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by dynamic light scattering and NMR. Inhibitory activity on CCR3 signaling was assessed in vitro using flow cytometry, confocal microscopy, and western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed using a triple allergen mouse asthma model. Results—R321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. IC50 values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of ERK1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo, R321 effectively blocks eosinophil recruitment into the lungs and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model. Conclusions—R321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism may hold significant therapeutic promise by eluding the formation of drug tolerance.

Item Type:	Article
Additional Information:	Published in final edited form as: J Allergy Clin Immunol. 2019 February ; 143(2): 669–680.e12. doi:10.1016/j.jaci.2018.05.003.
Keywords:	CCR3; eosinophil; allergic inflammation; asthma; biased antagonist; peptide nanoparticles; airway hyperresponsiveness;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13999
Identification Number:	https://doi.org/10.1016/j.jaci.2018.05.003
Depositing User:	Joanne Masterson
Date Deposited:	12 Feb 2021 10:59
Journal or Publication Title:	Journal of Allergy and Clinical Immunology
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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