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Title: Evolution of cyclic peptide Inhibitors of the Gag-TSG101 protein-protein interaction involved in HIV budding
Author: Lennard, Katherine Rachel
ISNI:       0000 0004 6500 8257
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2018
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In 2015, the World Health Organisation estimated that there were approximately 36.7 million people worldwide living with HIV. Although progress has been made in finding a cure, current treatment options rely on antiretroviral therapies that target different stages of the HIV lifecycle to control viral replication and reduce the risk of transmission. One stage of the HIV lifecycle that is not targeted by current antiretroviral therapies is the process by which nascent HIV virions assemble and bud from the plasma membrane. This process is governed by interactions between host and viral proteins and involves the recruitment the host cells' endosomal sorting complexes required for transport (ESCRT) machinery, through an interaction between the ubiquitin E2 variant (UEV) domain of TSG101 in ESCRT-1 and the p6 domain of the viral Gag protein. Previous research identified a cyclic peptide inhibitor (CP11) of the UEV-p6 interaction through a screening platform that combines the production of a randomised cyclic peptide library with a reverse two-hybrid system in E. coli. This research aimed to further improve the activity of CP11 through alanine-scanning to determine the active motif and to determine the binding partner biophysical assays, such as microscale thermophoresis. A more potent inhibitor was developed through the incorporation of unnatural amino acids that demonstrated improved inhibition of virus-like particle production in a cell-based assay with improved cell permeability over CP11. This work also provides a starting point for the development of small molecule inhibitors of a proteinprotein interaction that is vital to the HIV lifecycle.
Supervisor: Tavassoli, Ali Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available