Transcription Factor Inhibition
Metals in Medicine
The use of metals in medicine has grown impressively in recent years as the result of a greatly advanced understanding of the structures of biologically active metal complexes and metal-containing proteins. This area of research focuses on the interaction of inorganic therapeutic agents that can be specifically coupled to a biologically active site by cooperative ligation.
Cobalt(III) Schiff Base Complexes
The Meade lab seeks to understand and utilize Co(III)-Schiff base complexes (Co(III)-sb) as research tools and potential therapeutics. The complexes we study consist of a Co(III) center coordinated to an acetylacetonatoethylenediamine (acacen) backbone. The backbone can be modified to contain a targeting group, and axial ligand exchange dynamics can be exploited for biological or chemical utility.
Regulating Gene Transcription
Co(III)-sb complexes have been shown to irreversibly inhibit the activity of histidine-containing proteins by binding to histidine residues in the active site. Zinc finger transcription factors often contain a Cys2His2 type zinc finger that can be inhibited by Co(III)-sb. Co(III)-sb displaces Zn(II) and disrupts protein structure. For targeting, Co(III)-sb is tethered to the DNA consensus sequence of a specific transcription factor (making Co(III)-DNA). By inhibiting the activity of transcription factor proteins, gene transcription can be regulated. This can be exploited for use in cancer, developmental, and disease biology.
Epithelial-to-Mesenchymal Transition (EMT) Inhibition
Co(III)-DNA targeted to inhibit Snail family transcription factors has been synthesized and tested in Xenopus laevis. The Co(III)-DNA prevents Slug, Snail, and Sip1 from binding their DNA targets, while leaving other transcription factors unaffected. The attachment of the oligonucleotide to the Co(III) complex increases specificity 150-fold over the unconjugated complex. Slug, Snail, and Sip1 have been implicated in the regulation of epithelial-to-mesenchymal transition in development and cancer metastasis. A complex targeted to inactivate their transcriptional activity could prove valuable as an experimental tool and a cancer therapeutic.
Hedgehog Pathway Inhibition (Cancer)
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.
Inhibiting Amyloid-β Aggregation (Alzheimer’s)
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.