Date of Degree
Ruel Z. B. Desamero
Brian R. Gibney
Richard S. Magliozzo
Adam A. Profit
Peptide aggregation, amyloid, vibrational spectroscopy, hIAPP
Amyloid fibrils formed by of hIAPP1-37 (also known as amylin) has been linked to type-II diabetes mortalities and its formation was found to be related to the three aromatic residues in hIAPP1-37. In this dissertation, the role of aromatic amino acids, particularly that of Phe-23, and its various interactions to the self-assembly of human islet amyloid polypeptide (hIAPP)22-29 were investigated. Using a variety of spectroscopic techniques with emphasis to vibrational spectroscopy (FT-IR and Raman spectroscopies) in conjunction with computational methods, different factors leading to aggregation as well as its inhibition were identified. Among the driving forces identified are aromatic-π stacking between Phe residues which upon disruption by utilizing specially designed peptide-based inhibitors can lead to the abolition of aggregation propensity of hIAPP. In this work, three classes of peptide-based inhibitors were developed. The first group of inhibitors take advantage of the aromaticity of the Phe-23 residue of the hIAPP22-29 fragment that undergoes π-stacking upon aggregation. These peptides disrupt the aromaticity by introducing electron donating group (EDG) on Phe-23. Although these peptides showed no inherent amyloidogenic properties, their effectivity towards inhibition of full-length hIAPP aggregation was weak. The second batch of inhibitors, also based on hIAPP22-29 where benzenecarboxylic acid groups were conjugated to the N-terminus of the peptide fragment, showed a more promising inhibitory property towards full-length hIAPP aggregation. These peptides were designed to inhibit aggregation by interfering with the formation of the β-turn intermediate during the amyloid formation and at the same time providing electrostatic repulsion between amylin monomers. Although some of the conjugates showed inhibition, others showed promotion of amyloid formation. The third batch of peptide-based inhibitors were designed to exploit cationic-π interactions, a common interaction between aromatic and charged amino acid residues in polypeptides and proteins. In this batch of peptides, some inhibition was achieved primarily on the basis of increased solubility brought about by the peptide inhibitors binding to hIAPP via hydrophobic interactions.
Vedad, Jayson, "Mechanism and Development of Peptide-Based Inhibitors to Human Islet Amyloid Polypeptide (hIAPP) Self-Assembly" (2018). CUNY Academic Works.
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