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Design and Synthesis of Small Molecules for Specific Targeting of Proteins by Non-Covalent Interactions


Design and Synthesis of Small Molecules for Specific Targeting of Proteins by Non-Covalent Interactions

Hassanpour, Avid (2014) Design and Synthesis of Small Molecules for Specific Targeting of Proteins by Non-Covalent Interactions. PhD thesis, Concordia University.

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Hepatitis C virus (HCV) is a small, enveloped virus with a positive stranded
RNA genome that encodes a polyprotein of approximately 3000 amino acids. HCV polyprotein requires two distinct proteases for viral replication, the NS2 and the NS3. HCV NS2/3 protease is a cysteine protease that features a highly unusual active site where NS2 forms a dimer with the active site cysteine on one monomer and histidine and glutamate on the other. Initial in vitro studies for identification of site-derived cleavage products as inhibitors of NS2 protease showed that the decapeptide from the N-terminal cleavage inhibits the cleavage between NS2 and NS3 with an IC50 of 90 �M thus providing a useful starting point for the development of other inhibitors in the current studies. Our approach involves the synthesis of truncated NS2 site-derived
peptide cleavage products in order to evaluate the importance of hydrogen bonding interactions that are essential for host recognition and to aid in the reduction of the size of the polypeptide chain. Therefore, a number of truncated peptides were synthesized through solid-phase peptide synthesis. Furthermore, immunoblotting and UPLC-MS/MS methods were used for characterization of the NS2/3 protease and quantification of the peptide inhibitors. Our results demonstrate that a hexapeptide has encouraging potency towards inactivation of the NS2/3 auto-cleavage process.
The second project involves synthesis of islet amyloid polypeptide (IAPP) helical mimetics. Misfolding and aggregation of islet amyloid fibrils lead to the conversion of their secondary structure into cytotoxic �-sheet aggregates. Deposition of islet amyloid fibrils is related to the development and progression of type II diabetes, since their aggregation causes the impairment and death of the pancreatic beta cells. In order to prevent the formation of amyloid fibrils, we have designed aryl-substituted heteroaromatic core scaffolds to direct the secondary structure of pro-amyloidogenic peptides into non-amyloidogenic conformers to mimic and induce/stabilize the IAPP helical state. A range of 2,5-diarylated thiophenes were synthesized as small molecule mimetics of the �-helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide. 3-Substituted thiophene-2-carboxylic acids were used as key intermediates and functionalized by palladium decarboxylative cross-coupling and direct CH activation successively with overall yields ranging from 23 to 95%. The effect of the ligands on IAPP amyloid fibril formation was evaluated with the thioflavin T (ThT) fluorescence-based assay. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using �-pancreatic cells.

Divisions:Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry
Item Type:Thesis (PhD)
Authors:Hassanpour, Avid
Institution:Concordia University
Degree Name:Ph. D.
Date:27 May 2014
Thesis Supervisor(s):Forgione, Pat
ID Code:978797
Deposited On:20 Nov 2014 19:18
Last Modified:18 Jan 2018 17:47
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