Systematic development of peptide inhibitors targeting the CXCL12/HMGB1 interaction

During inflammatory reactions, the production and release of chemotactic factors guide the recruitment of selective leukocyte subpopulations. HMGB1 and the chemokine CXCL12, both released in the microenvironment, form a heterocomplex, which exclusively acts on the chemokine receptor CXCR4, enhancing cell migration and, in some pathological conditions such as Rheumatoid Arthritis, exacerbating 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 a novel peptide (HBP08), which binds HMGB1 with the highest affinity reported so far (Kd of 0.8 {+/-} 0.1 M), able to selectively inhibit the activity of the CXCL12/HMGB1 heterocomplex. The identification of this peptide represents an important step towards the development of innovative pharmacological tools for the treatment of severe chronic inflammatory conditions characterized by an uncontrolled immune response.