Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron

Abstract

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.

Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting

“…In addition, regardless of cell type, P-M-Dox showed greater internalization than P-Dox ( P < 0.01), which might be contributed to the lipophilic and highly cationic characters of MPP 35. , 53. .…”

Fluorescent and Photosensitizing Conjugates of Cell-Penetrating Peptide TAT(47-57): Design, Microwave-Assisted Synthesis at 60 °C, and Properties

“…Confirming our previous studies on microwave-assisted SPPS at 60 °C, 62 , 63 this combination was efficient and shortened the assembling of 1R in comparison to that performed earlier using traditional SPPS 23 , 33 or SPPS at 60 °C using conventional heating. 34 In fact, under the conditions used, the Fmoc-removal reactions were accomplished within 5 min and the acylation reactions were completed within 20 min, except for the acylation of the growing peptidyl-resin by Fmoc-Arg 7 (Pmc)-OH that had to be repeated for completion. Peptide cleavage from resin/full deprotection of about 10 mg of 1R gave crude product 1 containing the desired amidated TAT(47-57) as the major component, as shown by RP-HPLC (conditions in Table S1 ) and LC/ESI-MS (Figures S1 and S2 of Supporting Information ).…”

Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides

“…23 They have also proved that MPPs can be used for the mitochondrial delivery of different drugs like chlorambucil, platinum-based anticancer agent, doxorubicin, desferrioxamine. [24][25][26][27] In nature, the mitochondrial preproteins are synthesized in the cytosol with specific targeting signals. These signals are N-terminal presequences, which are proteolytically removed from the proteins by a protease in the matrix.…”