Inorganic Chemicals Commons^™

Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

Metallomic Approach To Mercury And Selenium In The Liver Tissue Of Psectrogaster Amazonica And Raphiodon Vulpinus From The Brazilian Amazon, Izabela Bataglioli, José Vieira, Joyce Da Siva, Luane Andrade, Victor Faria, Rebeca Corcoba, Ronaldo De Almeida, Luiz Zara, Marília Buzalaf, Jiri Adamec, Pedro Padilha

School of Medicine Faculty Publications

This paper reports the results of a mercury (Hg) and selenium (Se) metallomic study in the liver tissues of Psectrogaster amazonica and Raphiodon vulpinus from the Brazilian Amazon. Two-dimensional electrophoresis, graphite furnace atomic absorption spectrometry, and liquid chromatography-tandem mass spectrometry were performed. Hg and Se determinations allowed the calculation of Hg:Se and Se:Hg molar ratio and Se values for health benefits (Se HBVs). The Se:Hg values were >1 for both fish species, whereas the Se HBVs were >5 for P. amazonica and >10 for R. vulpinus, indicating that both possess Se reserves to control Hg toxicity. The metallomic data allowed …

Exploiting The Heavy Chain Glycans For The Improvement Of Radioimmunoconjugates, Cindy Rodriguez

Dissertations, Theses, and Capstone Projects

Radiolabeled antibodies have become indispensable tools in nuclear medicine. However, the natural roles of antibodies within the immune system mean that they have several intrinsic limitations as a platform for radiopharmaceuticals. A handful of recent preclinical studies suggest that binding by FcR and particularly FcyRI can affect the pharmacokinetic profiles of 89Zr-labeled radioimmunoconjugates. Fc receptors (FcR) are responsible for many of the interactions between immunoglobulins (IgG) and immune cells. In biomedicine, this interplay is critical to the activity of several types of immunotherapeutics; however, relatively little is known about how FcRs affect the in vivo performance of radiolabeled antibodies. Antibodies …

The Kinetic Modulation Of Α - Synuclein Fibrillation And Toxicity By 4-Phenylbutyric Acid, Kristos Awuah Baffour

Graduate Theses/Dissertations

ABSTRACT

The Protein misfolding and aggregation of alpha-synuclein (α-syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). 4-Phenylbutyrate (PBA), an FDA drug approved for treating urea cycle disorders, has garnered significant attention as a potential chemical chaperone for targeting alpha-synuclein (α-syn) aggregation. Using in vitro assays, we demonstrated that PBA treatment alters the pattern of α-syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K assay, surface plasmon resonance, and Nile red studies indicate that PBA interacts with the extensive …

Quantifying Metal Interactions With The Antimicrobial Peptide Calcitermin, Maria G. Aviles-Sandoval, Michael Stevenson

Featured Student Work

Antimicrobial Peptides (AMPs) are novel therapeutic agents that play important roles in the innate immune system with its ability to kill gram-positive and gram-negative bacteria. Antibiotics are losing their efficacy, thus requiring a larger dose of medicine for treatment resulting in the increase of antibiotic resistance. AMPs are an attractive approach for exploration due to their broad-spectrum activity and ease of synthesis. Furthermore, fewer bacteria have developed resistance to AMPs. Several AMPs have demonstrated increased antimicrobial activity with metal ions, like Zn(II) and Cu(II) binding to the peptide. In this study, we performed the purification of Calcitermin through high-performance liquid …

Designing And Synthesizing A Warhead-Fragment Inhibitory Ligand For Ivyp1 Through Fragment-Based Drug Discovery, Samuel Moore

Symposium of Student Scholars

Fragment-based drug discovery (FBDD) is a powerful tool for developing anticancer and antimicrobial agents. Within this, magnetic resonance spectroscopy (NMR) provides a comprehensive qualitative and quantitative approach to screening and validating weak and robust binders with targeted proteins, making NMR among the most attractive strategies in FBDD. Inhibitor of vertebrate lysozyme (Ivyp1) of P. aeruginosa serves as an excellent target because of its active cellular location and implications in clinical prognosis for cystic fibrosis and immunocompromised patients. This study uses current NMR and biophysical techniques to develop a covalent, fragment-linked warhead inhibitor for Ivyp1 through synthetic methods, warhead linking, and …

Synthesis Of Selenotryptophan For Protein Elucidation, James P. Reiselman

[Archive] Belmont University Research Symposium (BURS)

Through complex intermolecular and intramolecular forces, proteins conformationally change to form complex 3-d geometry that carries out biochemical processes and mapping their structures is becoming a field of interest in the biological community. Techniques for modeling protein’s structure typically follow the path of X-ray crystallography, which has an intrinsic phase problem that can make reading the electron density map they produce very difficult. This can be mitigated by appending a heavy-atom containing amino acid analogue into a crystal sample of the protein being studied. A selenium containing tryptophan analogue will be synthesized to be appended into proteins as a chemical …

Caspases And Cancer: Connections Through Circular Dichroism Spectroscopy, Sarah M. Hethcox

Honors College Theses

While excessive cell death inevitably leads to negative effects, the endurance of damaged cells in the presence of death signals can be equally detrimental to health. Apoptosis, or programmed cell death, is a highly regulated process in which cues from within or from outside a cell can trigger an irreversible sequence of signals that carry out cell destruction known as the apoptotic cascade. A group of enzymes called caspases play a vital role in this cascade with some participating as initiators and others acting as effectors of protein cleavage and intracellular breakdown. Although it is normal for the activity of …

Diversity Oriented Synthesis, Characterization And Anti-Cancer Activity Of Killer Peptide Nucleolipid Bioconjugates, Niki K. Rana

Seton Hall University Dissertations and Theses (ETDs)

The killer peptide sequence D-(KLAKLAK)₂ has been originally designed and developed as an antibacterial agent. Despite having excellent cytotoxicity towards bacteria, this sequence maintains low cell cytotoxity in malignant mammalian cell types such as cancer. The chemical basis for its selectivity has been attributed to its poly(cationic) amphiphilic nature, which facilitates cell permeability across the negatively charged bacterial membrane, but with limited permeability across the zwitterionic membrane of mammalian cells. The positively charged D-(KLAKLAK)₂ sequence has been found to accumulate on the surface of the mitochondria causing dissipation of the negatively charged mitochondrial membrane potential. This charge disruption …

Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying

Honors Thesis

The Zn(II) metal ion has been shown to interact with Islet Amyloid Polypeptide (IAPP), a protein implicated in the progression of Type II Diabetes Mellitus, in such a way as to prevent the protein from aggregating into toxic fibers. We set out to find whether other metal ions might similarly prevent IAPP aggregation. Using Thioflavin T (ThT) spectroscopic assays, which measure fluorescence of ThT upon binding to aggregated IAPP, we observed a decrease in aggregation when incubated with Zn(II), Cu(II), Ni(II), and Sn(II). Atomic Force Microscopy (AFM), which can visualize fibril formation, revealed that the metals were not inhibiting IAPP …