Alta Roxana Y P, Vitorino Hector A, Goswami Dibakar, Liria Cleber W, Wisnovsky Simon P, Kelley Shana O, Machini M Terêsa, Espósito Breno P
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
PLoS One. 2017 Feb 8;12(2):e0171729. doi: 10.1371/journal.pone.0171729. eCollection 2017.
Desferrioxamine (DFO) is a bacterial siderophore with a high affinity for iron, but low cell penetration. As part of our ongoing project focused on DFO-conjugates, we synthesized, purified, characterized and studied new mtDFOs (DFO conjugated to the Mitochondria Penetrating Peptides TAT49-57, 1A, SS02 and SS20) using a succinic linker. These new conjugates retained their strong iron binding ability and antioxidant capacity. They were relatively non toxic to A2780 cells (IC50 40-100 μM) and had good mitochondrial localization (Rr +0.45 -+0.68) as observed when labeled with carboxy-tetramethylrhodamine (TAMRA) In general, mtDFO caused only modest levels of mitochondrial DNA (mtDNA) damage. DFO-SS02 retained the antioxidant ability of the parent peptide, shown by the inhibition of mitochondrial superoxide formation. None of the compounds displayed cell cycle arrest or enhanced apoptosis. Taken together, these results indicate that mtDFO could be promising compounds for amelioration of the disease symptoms of iron overload in mitochondria.
去铁胺（DFO）是一种对铁具有高亲和力但细胞穿透性低的细菌铁载体。作为我们正在进行的专注于DFO缀合物项目的一部分，我们使用琥珀酸接头合成、纯化、表征并研究了新的线粒体靶向去铁胺（mtDFO，即与线粒体穿透肽TAT49 - 57、1A、SS02和SS20缀合的DFO）。这些新的缀合物保留了其强大的铁结合能力和抗氧化能力。它们对A2780细胞相对无毒（IC50为40 - 100 μM），并且在用羧基四甲基罗丹明（TAMRA）标记时显示出良好的线粒体定位（Rr为 +0.45 - +0.68）。总体而言，mtDFO仅引起适度水平的线粒体DNA（mtDNA）损伤。DFO - SS02保留了母体肽的抗氧化能力，这通过抑制线粒体超氧化物的形成得以体现。这些化合物均未表现出细胞周期停滞或增强的细胞凋亡。综上所述，这些结果表明mtDFO可能是改善线粒体铁过载疾病症状的有前景的化合物。
