An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation.
10.1016/j.apsb.2020.12.005
- Author:
Mirja HARMS
1
;
Monica M W HABIB
2
;
Simona NEMSKA
3
;
Antonella NICOLÒ
4
;
Andrea GILG
1
;
Nico PREISING
5
;
Pandian SOKKAR
6
;
Sara CARMIGNANI
7
;
Martina RAASHOLM
8
;
Gilbert WEIDINGER
8
;
Gönül KIZILSAVAS
9
;
Manfred WAGNER
9
;
Ludger STÄNDKER
5
;
Ashraf H ABADI
2
;
Hassan JUMAA
4
;
Frank KIRCHHOFF
1
;
Nelly FROSSARD
3
;
Elsa SANCHEZ-GARCIA
6
;
Jan MÜNCH
1
Author Information
1. Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.
2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
3. Laboratoire D'Innovation Thérapeutique, UMR7200 CNRS/Université de Strasbourg and LabEx MEDALIS, Faculté de Pharmacie, Illkirch 67412, France.
4. Institute of Immunology, Ulm University Medical Center, Ulm 89081, Germany.
5. Core Facility Functional Peptidomics, Ulm University Medical Center, Ulm 89081, Germany.
6. Center of Medical Biotechnology, University of Duisburg-Essen, Duisburg 47057, Germany.
7. Max-Planck-Institut für Molekulare Physiologie, Dortmund 44227, Germany.
8. Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
9. Max Planck Institute for Polymer Research, Mainz 55128, Germany.
- Publication Type:Journal Article
- Keywords:
Allergy;
Asthma;
Atopic dermatitis;
CXCR4 antagonist;
Inflammation
- From:
Acta Pharmaceutica Sinica B
2021;11(9):2694-2708
- CountryChina
- Language:English
-
Abstract:
Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted.
