Al Taleb Zukaa, Hierlmeier Ina, Heilmann Heiko, Jung Martin, Bartholomä Mark, Bufe Bernd
Department of Informatics and Microsystems Technology, University of Applied Sciences Kaiserslautern, 66482, Zweibrücken, Germany.
Department of Nuclear Medicine, Medical Center, Saarland University, 66421, Homburg, Germany.
Sci Rep. 2025 Sep 12;15(1):32479. doi: 10.1038/s41598-025-18831-z.
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.
细菌信号肽是甲酰肽受体（FPRs）的一大类高亲和力配体。这些受体在胶质母细胞瘤和其他几种肿瘤类型的表面高度富集。在本研究中，我们评估了细菌信号肽作为一类尚未充分探索的高亲和力FPR激动剂在放射性药物应用中的潜力。我们测试了一系列细菌信号肽及其荧光标记衍生物，以确定能够进行化学修饰而亲和力不发生大幅损失的肽残基。然后，我们开发了一种对FPR1具有超过1000倍选择性的选择性荧光肽衍生物，它在低纳摩尔浓度下能快速结合，并形成可稳定存在长达72小时的受体-配体复合物。这种肽探针能有效结合人胶质瘤细胞系U87-MG，并能有效穿透源自U87-MG细胞的球体。最后，我们设计了一种具有相似亲和力的相应金属螯合物-肽共轭物，它能被FPR1转染的HEK293T细胞和天然表达FPR1的U87-MG细胞摄取。在健康小鼠中进行的平面闪烁扫描初步研究表明，健康器官中没有明显的摄取或滞留，这表明细菌信号肽确实可能是开发放射性药物的一个有趣工具。
