1. Systematic Development of Peptide Inhibitors Targeting the CXCL12/HMGB1 Interaction
- Author
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Maura Garofalo, Mattia Pedotti, Enrico M.A. Fassi, Andrea Cavalli, Mariagrazia Uguccioni, Valentina Cecchinato, Luca Varani, Jacopo Sgrignani, Luca Simonelli, Gabriela Danelon, Gianluca D'Agostino, and Giovanni Grazioso
- Subjects
Receptors, CXCR4 ,Chemokine ,Cell ,chemical and pharmacologic phenomena ,HMGB1 ,CXCR4 ,Cell Line ,Mice ,Chemokine receptor ,Immune system ,Cell Movement ,Drug Discovery ,medicine ,Animals ,Humans ,Amino Acid Sequence ,HMGB1 Protein ,biology ,Chemistry ,Cell migration ,Chemotaxis ,Chemokine CXCL12 ,Cell biology ,Molecular Docking Simulation ,medicine.anatomical_structure ,biology.protein ,Molecular Medicine ,Peptides ,Protein Binding - Abstract
During inflammatory reactions, the production and release of chemotactic factors guide the recruitment of selective leukocyte subpopulations. The alarmin HMGB1 and the chemokine CXCL12, both released in the microenvironment, can form a heterocomplex, which exclusively acts on the chemokine receptor CXCR4, enhancing cell migration, and in some pathological conditions such as rheumatoid arthritis exacerbates the immune response. An excessive cell influx at the inflammatory site can be diminished by disrupting the heterocomplex. Here, we report the computationally driven identification of the first peptide (HBP08) binding HMGB1 and selectively inhibiting the activity of the CXCL12/HMGB1 heterocomplex. Furthermore, HBP08 binds HMGB1 with the highest affinity reported so far (Kd of 0.8 ± 0.4 μM). The identification of this peptide represents an important step toward the development of innovative pharmacological tools for the treatment of severe chronic inflammatory conditions characterized by an uncontrolled immune response.
- Published
- 2021