Systematic Development of Peptide Inhibitors Targeting the CXCL12/HMGB1 Interaction
Jacopo Sgrignani1, Valentina Cecchinato1, Enrico M A Fassi1,2
1Institute for Research in Biomedicine, Università della Svizzera italiana, CH-6500 Bellinzona, Switzerland.
Insights
Researchers identified a novel peptide, HBP08, that disrupts the CXCL12/HMGB1 complex. This finding offers a new therapeutic strategy for chronic inflammatory diseases by controlling excessive immune cell migration.
Area of Science:
- Immunology
- Pharmacology
- Computational Biology
Background:
- Inflammatory reactions involve chemotactic factors guiding leukocyte recruitment.
- The alarmin HMGB1 and chemokine CXCL12 form a heterocomplex that enhances cell migration via CXCR4, exacerbating conditions like rheumatoid arthritis.
- Disrupting this heterocomplex can reduce excessive inflammatory cell influx.
Purpose of the Study:
- To identify a molecule that selectively inhibits the CXCL12/HMGB1 heterocomplex.
- To develop novel pharmacological tools for treating chronic inflammatory conditions.
Main Methods:
- Computationally driven identification of peptides targeting the CXCL12/HMGB1 heterocomplex.
- Affinity determination of the identified peptide (HBP08) to HMGB1.
Main Results:
- The first peptide, HBP08, was identified that binds HMGB1 and selectively inhibits the CXCL12/HMGB1 heterocomplex.
- HBP08 exhibits the highest reported affinity for HMGB1 (Kd of 0.8 ± 0.4 μM).
Conclusions:
- The identification of HBP08 is a significant advancement in developing targeted therapies for chronic inflammatory diseases.
- This peptide offers a potential strategy to manage uncontrolled immune responses by modulating leukocyte migration.
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.
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