Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron.
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.
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.
Roxana Y P
RY
Alta
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Hector A
HA
Vitorino
Bhabha Atomic Research Centre, Mumbai, Maharashtra, India.
Dibakar
D
Goswami
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Cleber W
CW
Liria
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Simon P
SP
Wisnovsky
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.|Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Shana O
SO
Kelley
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
M Terêsa
MT
Machini
Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
Breno P
BP
Espósito
D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013481:Superoxides / Q000378:metabolism
D017304:Annexin A5; D000975:Antioxidants; D007502:Iron Chelating Agents; D010455:Peptides; D013481:Superoxides; D007501:Iron; D003676:Deferoxamine