Department of Chemistry, RCSI University of Medicine and Health Sciences, 123, St. Stephen's Green, D02 YN77 Dublin, Ireland.
SSPC (Synthesis and Solid State Pharmaceutical Centre) Research Centre, V94 T9PX Limerick, Ireland.
Int J Mol Sci. 2024 Nov 19;25(22):12411. doi: 10.3390/ijms252212411.
Cationic antimicrobial peptides (AMPs), also called host defence peptides, have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were conjugated to L-K6, a lysine/leucine-rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components.
阳离子抗菌肽（AMPs），也称为宿主防御肽，具有抗菌和抗癌活性。将 AMP 与具有互补活性的生物活性分子偶联可以解决肽候选物的一些临床限制。这种方法在 AMP 的抗菌应用中得到了特别应用，但在抗癌候选物的生成中相对较少探索。在这项研究中，两种地衣酸衍生物，分别基于腙噻唑和苄叉呋喃酮药效团部分，通过货物分子内在驱动的新型吡唑键连接到富含赖氨酸/亮氨酸的 AMP L-K6 上。两种成分，地衣酸衍生物和肽，通过靶向人 DNA 修复酶酪氨酸-DNA 磷酸二酯酶 1（TDP1）和通过 DNA 损伤，分别针对癌细胞具有选择性活性。基于腙键的两种缀合物表现出多种效应，从降低母体药物的活性到其保留甚至增强。值得注意的是，与它们的单个成分相比，缀合物保留了一些抗 TDP1 活性，并对神经胶质瘤细胞显示出中等甚至更高的细胞毒性。
