Peptides have traditionally been perceived as poor drug candidates due to unfavorable
characteristics mainly regarding their pharmacokinetic behavior, including plasma stability,
membrane permeability and circulation half-life. Nonetheless, in recent years, general strategies
to tackle those shortcomings have been established, and peptides are subsequently gaining
increasing interest as drugs due to their unique ability to combine the advantages of antibodies
and small molecules. Macrocyclic peptides are a special focus of drug development efforts due
to their ability to address so called ‘undruggable’ targets characterized by large and flat protein
surfaces lacking binding pockets. Especially in the field of complement therapeutics this has
resulted in two remarkable approvals of cyclic peptides, Pegcetacoplan and Zilucoplan. Both
are the first cyclic peptides reaching the market which have been de-novo evolved by display
methods.

Our group focuses on the development of cyclic peptides by using chemically modified phage
display and computational design, with special emphasis on complement modulation. In a
recent project we focused on the complement receptors CR3 and CR4. These members of the
β2-integrin family are involved in complement-dependent phagocytosis and leukocyte
adhesion, migration, and activation, thereby playing important roles in immune surveillance and
inflammation. The direct involvement of β2-integrin receptors in autoimmune, inflammatory,
and age-related diseases render them interesting drug targets, however their complex interplay
to a multitude of endogenous protein ligands is not well understood. By developing CR3-
targeting cyclic peptides, we aim to gain more insights in its ligand binding sites, and to
ultimately modulate leukocyte function. Phage display screening against CR3 αMI identified a
set of cyclic peptides with direct binding to the αMI domain and able to compete with
endogenous ligands. We conducted structure-activity relationship and plasma stability studies
and investigated modulating activities in functional adhesion assays.