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A Novel Strategy for the Synthetic Selection of Enhanced Therapeutic Aptamers

Paul, Alexandra Rosie (2022) A Novel Strategy for the Synthetic Selection of Enhanced Therapeutic Aptamers. Doctor of Philosophy (PhD) thesis, University of Kent,. (doi:10.22024/UniKent/01.02.97439) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:97439)

Language: English

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The epidermal growth factor receptor protein (EGFR) promotes tumorigenesis in many cancers, including breast, lung, colon and glioblastoma. Deregulation of EGFR activity in cancer is mainly due to point mutation, kinase domain deletion or gene amplification. It is essential to have EGFR-targeted therapies because it is among the most commonly altered genes in cancer. Aptamers are single-stranded oligonucleotide sequences that bind with high affinity and specificity to diverse targets. The recognition capacity of aptamers can be harnessed for therapeutic agents. The chemistry of aptamers is largely limited to that of nucleic acids, and although non-natural modifications of nucleic acids are known to enhance aptamer affinity, there is not yet a technology for selecting the right modifications amongst billions of possibilities.

This project aims to develop the first general method for the discovery of nucleoside modifications that increase aptamer binding efficacy. A library will be created of over 65,000 different chemical modifications on a known aptamer sequence (MinE07), which binds to EGFR protein. The modifications will use different types of chemistry to see how they will affect the binding and folding of the aptamer MinE07, aiming to improve the binding between MinE07 and EGFR. These will be attached on beads such that each bead displays millions of copies of a single aptamer sequence. The selection will then be carried out using a flow cytometer (FACS) to separate out the aptamer sequences with the highest affinity for EGFR from the one-bead-one-sequence aptamer library. These will then be identified using mass spectrometry. These top selected aptamer sequences will be subjected to biophysical and biological testing. This research provides a new method for synthesising and screening in a short space of time large drug candidate libraries producing new drug candidates and impacting drug discovery processes.

Item Type: Thesis (Doctor of Philosophy (PhD))
Thesis advisor: Serpell, Christopher
Thesis advisor: Garrett, Michelle
DOI/Identification number: 10.22024/UniKent/01.02.97439
Uncontrolled keywords: Aptamers, Flow Cytometry, Drug Discovery, Cancer, Chemistry, Chemical Biology
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Chemistry and Forensics
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 17 Oct 2022 08:51 UTC
Last Modified: 18 Oct 2022 09:32 UTC
Resource URI: (The current URI for this page, for reference purposes)
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