The Design And Synthesis Of Inhibitors Of Hiv-1 Viral Entry And Photoaffinity Labeled Probes For Structural Elucidation Of The Hiv-1 Env

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Chemistry
Discipline
Subject
Organic Chemistry
Funder
Grant number
License
Copyright date
2020-02-07T20:19:00-08:00
Distributor
Related resources
Author
Gaffney, Althea Erica
Contributor
Abstract

An estimated 38 million people globally are currently living with Human Immunodefficiency Virus (HIV-1). While HIV-1 can be effectively treated with antiretroviral therapy (ART), the efficacy of ART is challenged by its cost, required access to regular care, and the onset of viral resistance. Methods to both prevent and cure HIV-1 infection are thus desperately needed. Three such strategies are described herein. Firstly, small molecules which mimic CD4 have been developed which inhibit HIV-1 infection. Notably, these compounds increase the ability of the Env trimer to sample a more open conformation which sensitizes the Env to antibody mediated neutralization and elimination (ADCC). Secondly, HIV-1 infection inhibition and lysis of HIV-1 virions has been accomplished via the design, synthesis and validation of a family of small molecule “Dual-Action Virucidal Entry Inhibitors” (DAVEIs). These compounds, comprised of a small molecule warhead tethered to a segment of the gp41 MPER denoted Trp3, have achieved irreversible lytic inactivation of HIV-1 virions. Finally, small molecules appended with photoactivatable crosslinking moieties were developed which stabilize the Env conformation recognized by most broadly neutralizing antibodies. Importantly, no structure of this Env conformation is reported in the literature. This work is expected to enable both structural elucidation of this critical Env conformation and aid the development of an HIV-1 vaccine.

Advisor
Amos B. Smith, III
Date of degree
2019-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation