Assessing the potential of bacterial signal peptides for radiopharmaceutical applications

Bacterial signal peptides are a large group of high-affinity ligands for formyl peptide receptors (FPRs). These receptors are highly enriched on the surface of glioblastomas and several other tumor types. In this study, we evaluated the potential of bacterial signal peptides, a yet relatively unexplored class of high affinity FPR agonist for radiopharmaceutical applications. We tested a range of bacterial signal peptides and their fluorescently labeled derivatives to identify peptide residues that allow chemical modification without drastic loss of affinity. We then developed a selective fluorescent peptide derivative with more than 1000-fold selectivity towards FPR1, which binds rapidly at low nanomolar concentrations and forms stable receptor-ligand complexes that can persist for up to 72 h. This peptide probe effectively bound to a human glioma cell line U87-MG and efficiently penetrated spheroids derived from U87-MG cells. Finally, we have designed a corresponding metal chelate-peptide conjugate with similar affinity that is taken up by FPR1-transfected HEK293T cells and naturally FPR1-expressing U87-MG cells. A pilot study with planar scintigraphy in healthy mice showed no substantial uptake or retention in healthy organs, suggesting that bacterial signal peptides could indeed be an interesting tool for the development of radiopharmaceuticals.