Transcription Factor Inhibition
Cancer Hedgehog Pathway Inhibition
Targeted Co(III)-DNA has also shown remarkable specificity in inhibiting Ci protein, the final step in the Drosophila hedgehog signaling pathway. The hedgehog signaling pathway is overactivated in cancers such as basal cell carcinoma (skin) and medulloblastomas (brain), so inhibiting the pathway has therapeutic potential. Studies are currently underway to inhibit Gli protein, the mammalian analog of Ci. In order to deliver this to mammalian tissues, gold nanoparticles are being utilized.
Injection of Co(III)-Ci but not Co(III)-CiMut is able to phenocopy loss of ci function in vivo. Drosophila cuticle mounts showing denticle belt patterning of 48 h old embryos. Wild-type embryos between 0 and 45 min old were microinjected with 1μM (C) Co(III)-CiMut or (D) Co(III)-Ci, allowed to develop for 48 h, mounted and imaged by phase contrast light microscopy. Arrow points to denticle belt fusion characteristic of a ci mutant.
Inhibiting Amyloid-β Aggregation
Oligomers of the Aβ42 peptide are significant neurotoxins linked to Alzheimer’s disease (AD). Histidine (His) residues present at the N terminus of Aβ42 are believed to influence toxicity by either serving as metal–ion binding sites (which promote oligomerization and oxidative damage) or facilitating synaptic binding. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co(III)-sb complexes could interact with the His residues in a truncated Aβ16 peptide representing the Aβ42 N terminus. Coordination of Co(III)-sb complexes altered the structure of Aβ42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of Aβ correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co(III)-sb complexes in anti-AD therapeutic approaches.
Proposed scheme of the modulation of Aβ activity by Co–acacen. Co–acacen is believed to coordinate the His residues of Aβ through the two axial positions. Computational studies suggest the simultaneous coordination of His6 and either His13 or His14 as the most stable conformation. His-coordination alters the Aβ structure, disrupting oligomerization pathways and synaptic binding.