Date of Award
Spring 4-22-2025
Degree Type
Dissertation/Thesis
Degree Name
Masters in Chemical Sciences
Department
Chemistry and Biochemistry
Committee Chair/First Advisor
Dr.Mohammad Halim
Second Advisor
Dr. Christopher Dockery
Third Advisor
Dr. Madalynn Marshall
Abstract
Alzheimer’s disease (AD) is defined as a progressive neurological disorder that has adverse effects on one’s cognitive function over time. Currently identified as the prevalent antecedent of dementia, this disease is ranked seventh in the leading causes of death by the CDC. Since its discovery in 1906, there’s been an 145% increase in deaths observed by researchers. Unfortunately, scientists have been unsuccessful in both curing and eradicating the diseases’ harsh symptoms. Amyloid-Beta (Ab) is a protein who accumulates into neurofibrillary tangles and extracellular plaques when sliced by b- and g- secretases. It is placed at the forefront as the cause of AD. Fortunately, the inhibition of Ab has been identified as a promising avenue in the fight for therapeutics. In this research, various peptides are synthesized and investigated to analyze their impact on binding affinity to Ab via liquid chromatography- mass spectrometry (LC-MS) selected ion monitoring (SIM) assays. The aim of this project is to develop peptide-based inhibitors by modifying previously tested peptide sequences that were successful in targeting and inhibiting Ab. Kinetic dissociation constant (Kd) is the factor used to measure the binding affinity between Ab and successfully synthesized peptides. Unbiased molecular docking was used to predict and support the exhibited binding strength and interactions of synthesized peptides. Linear peptides 1 through 4 (LP-1 to -4) and cyclic peptide 1 (CP-1) was synthesized, characterized, and analyzed. LP-1 presented the strongest binding affinity of all peptides with a Kd value of 1.73 nM, followed by LP-3 with a Kd value at 19.69 nM, and LP-4 at 24.90 nM. CP-1 displayed a weaker binding in comparison to its linear counterpart at 49.12 nM, and LP-2 displayed the weakest binding interactions of all peptides at 50.90 nM. This data identified viable peptides for further research toward Ab inhibition, thus providing new avenues to aid in the fight against AD.