New Class of CXCR4 Antagonists May Prevent Airway Inflammation and Atopic Dermatitis


CXCR4 / CXCL12 aberrant signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has already been identified as an endogenous peptide antagonist and reverse agonist of CXCR4 and is a promising compound for the development of improved analogs for the treatment of diseases associated with CXCR4.

To generate optimized EPI-X4 derivatives, the authors of this article performed molecular docking analysis to identify the main patterns of EPI-X4 / CXCR4 interaction. The subsequent rational design of the drug made it possible to increase the anti-CXCR4 activity of EPI-X4.

The JM # 21 EPI-X4 derivative bound to CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved CXCR4 small molecule antagonist AMD3100. EPI-X4 JM # 21 did not exert toxic effects on zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the respiratory tract of animals in a model of asthmatic mouse. In addition, topical administration of the optimized EPI-X4 derivative effectively prevented skin inflammation in a mouse model of atopic dermatitis.

Thus, the rationally designed EPI-X4 JM # 21 is a potent new CXCR4 antagonist and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. The further clinical development of this new class of CXCR4 antagonists for the treatment of atopic dermatitis, asthma and other diseases associated with CXCR4 is highly warranted.


Journal reference:

Damage, M., et al. (2021) An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and respiratory tract inflammation. Acta Pharmaceutical Sinica B.

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