Cobalt (III) Schiff-base Complexes as Inhibitors of Pathogenic MetalloproteinsPublic
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Cobalt(III) Schiff-base complexes (Co(III)-sb) have been utilized in the literature as antibacterial, antiviral, and inhibitory agents. Recent work has utilized their ability to displace endogenous metals from metalloproteins that exhibit aberrant gain of function pathologies in human disease. Specifically, in this dissertation Co(III)-sb has been applied as inhibitors of pathogenic metalloproteins in two main systems: 1) The aggregation of the small disordered peptide, amyloid-beta which is implicated in Alzheimer’s Disease (AD) 2) The zinc finger transcription factor Gli1 which is overexpressed in Basal Cell Carcinoma (BCC), Medulloblastoma, and pancreatic adenocarcinomas. In Chapter 2, it was shown that Co(III)-sb coordination can influence the on the monomer dynamics, secondary structure, and aggregation properties of amyloid-beta. Molecular dynamics (MD) and bulk kinetic aggregation assays demonstrated that Co(III)-sb inhibits the formation of the beta-sheet secondary structure that initiate aggregation. In Chapter 3, detailed kinetic fluorescent assays were employed to demonstrate the Co(III)-sb modulates the bulk aggregation pathway of amyloid-beta and favors the formation of large non-amyloidogenic aggregates with reduced cyto-toxicity. In Chapter 4, Co(III)-sb was applied to displace the endogenous structural zinc ions from the Gli1 zinc finger transcription factor. MD and spectroscopic studies showed that Co(III)-sb can displace endogenous Zn(II) ions from the zinc finger domain and degrade the alpha helix structure necessary for recognition of its consensus sequence DNA. In Chapter 5, an exploratory study of Co(III)-sb complexes with small peptide targeting moieties was conducted in order to increase specificity and efficacy to amyloid-beta. Replica Exchange Molecular Dynamics (REMD) and bulk kinetic assays were used to evaluate the effect of targeted Co(III)-sb complexes on the free energy landscape of amyloid-beta. It was found that targeting moieties increased the interaction energy between Co(III)-sb and the hydrophobic regions of amyloid-beta. REMD simulations showed that Co(III)-sb complex lead reduced access to conformational states that are believed to seed aggregation.
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