Dissertation
Pharmacological and biological inhibition of HIV-1 entry
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000924
Abstract
Even after 40 years, the HIV-1 pandemic continues to have devastating effects worldwide. An attractive target for pre- and post-exposure therapies, including vaccines, is the Env glycoprotein complex. The Env glycoprotein complex is the only viral protein present on the surface of a virion and is the molecular machine that orchestrates the entry process. We have previously extended and optimized the piperazine class of entry inhibitors using computationally aided design. Here, we demonstrate unique and differential effects of these compounds on the gross structure of the HIV-1 Env complex. From our new chemotypes, the novel compound SC28, had the most pronounced effect on the conformation of Env. Indeed, it pushed the Env conformational equilibrium into a homogenous, stabilized, and closed state as judged by multiple methods. Since a stable, closed form of Env is considered to be the best vaccine immunogen for eliciting broadly neutralizing antibodies (bNAbs), and a vaccine is regarded as the best method to control the HIV-1 pandemic, we explored utilizing an SC28-liganded, closed Env immunogen to identify Env-targeting Abs. Using phage display technology against a pool of SC28-liganded Env, we identified a novel scFv termed MC01 that interacts specifically with the HIV-1 Env and has broadly neutralizing capabilities against isolates most representative of the HIV-1 global burden. These findings support the continued exploration of compounds that shift the conformational equilibrium of the HIV-1 Env as a novel strategy to improve future entry inhibitors and to potentiate vaccine efforts.
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Details
- Title
- Pharmacological and biological inhibition of HIV-1 entry
- Creators
- Megan E. Meuser
- Contributors
- Simon Cocklin (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 280 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991016053431404721