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.
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.