肽
药效团
化学
结合
生物化学
抗菌剂
细胞毒性
抗菌肽
小分子
组合化学
体外
有机化学
数学分析
数学
作者
Siobhán O’Flaherty,Olga A. Luzina,Nadezhda S. Dyrkheeva,Ysaline Krier,Jérôme Leprince,Alexandra L. Zakharenko,Аndrey G. Pokrovsky,Аndrey G. Pokrovsky,Olga I. Lavrik,Нариман Ф. Салахутдинов,Mihayl Varbanov,Marc Devocelle,Константин П. Волчо
标识
DOI:10.3390/ijms252212411
摘要
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.
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