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• W3081691649 abstract "Abstract Background Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes including chronic inflammatory diseases. Thus, the chemokine receptor CXCR4 is a promising target for the therapy of inflammatory disorders, such as atopic dermatitis or allergic asthma. A natural fragment of serum albumin, named EPI-X4, has previous been identified as endogenous peptide antagonist and inverse agonist of CXCR4. The endogenous CXCR4 antagonist provides a promising basis for the development of improved analogues for the therapy of inflammatory diseases. Objective To increase the anti-CXCR4 activity of EPI-X4 and to evaluate the therapeutic potential of optimized analogs in mouse models of atopic dermatitis and asthma. Methods Molecular docking analysis of the interaction of EPI-X4 with CXCR4 was performed to define critical interaction motifs and to rationally design analogs with increased activity. EPI-X4 derivatives were synthesized and CXCR4 binding and antagonizing activity determined in assays for antibody competition, inhibition of CXCR4-mediated HIV-1 infection, CXCL12-dependent Ca 2+ mobilization, ERK and AKT phosphorylation and cell migration. Toxicity of peptides was evaluated in zebrafish embryos. The therapeutic efficacy of the lead peptide EPI-X4 JM#21 was determined in mouse models of atopic dermatitis and asthma. Results Docking analysis identified key interaction motifs of EPI-X4/CXCR4. Rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4 and resulted in the generation of the lead analog JM#21, which bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. JM#21 did not exert toxic effects in zebrafish embryos and efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Moreover, EPI-X4 and its improved derivative suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Conclusion The rationally designed EPI-X4 derivative JM#21 is a 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. Graphical Abstract" @default.
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• W3081691649 date "2020-08-29" @default.
• W3081691649 modified "2023-09-30" @default.
• W3081691649 title "An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation" @default.
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• W3081691649 cites W1973196959 @default.
• W3081691649 cites W1975696541 @default.
• W3081691649 cites W1978836367 @default.
• W3081691649 cites W1979856307 @default.
• W3081691649 cites W1981149366 @default.
• W3081691649 cites W1983919032 @default.
• W3081691649 cites W1995237768 @default.
• W3081691649 cites W2001009396 @default.
• W3081691649 cites W2007114641 @default.
• W3081691649 cites W2011403845 @default.
• W3081691649 cites W2015784582 @default.
• W3081691649 cites W2029667189 @default.
• W3081691649 cites W2033185851 @default.
• W3081691649 cites W2039710848 @default.
• W3081691649 cites W2046318425 @default.
• W3081691649 cites W2048566951 @default.
• W3081691649 cites W2056369613 @default.
• W3081691649 cites W2070132846 @default.
• W3081691649 cites W2079118227 @default.
• W3081691649 cites W2080719056 @default.
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• W3081691649 cites W2085551556 @default.
• W3081691649 cites W2100386815 @default.
• W3081691649 cites W2113394933 @default.
• W3081691649 cites W2114805956 @default.
• W3081691649 cites W2131644278 @default.
• W3081691649 cites W2132974151 @default.
• W3081691649 cites W2135338948 @default.
• W3081691649 cites W2136332525 @default.
• W3081691649 cites W2143761974 @default.
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• W3081691649 cites W2153983456 @default.
• W3081691649 cites W2155728143 @default.
• W3081691649 cites W2157425818 @default.
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• W3081691649 cites W2295828909 @default.
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• W3081691649 cites W2468216259 @default.
• W3081691649 cites W2550355067 @default.
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• W3081691649 doi "https://doi.org/10.1101/2020.08.28.272781" @default.
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