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Dissertation
Investigation into the mechanism of a novel HIV-1 fusion inhibitor, SC12
Doctor of Philosophy (Ph.D.), Drexel University
29 Nov 2016
DOI:
https://doi.org/10.17918/etd-7177
Abstract
Due to the emergence of drug-resistant viruses and problems with drug side effects, new drugs and drug targets are constantly required in the battle against HIV-1/AIDS. The entry of the virus into host cells and the molecular machine that facilitates this process, the Env glycoproteins, are extremely attractive and underexploited therapeutic targets. Env glycoproteins, gp120 and gp41, are assembled into trimeric complexes on the virion surface. The attachment of virus to target cells triggers conformational changes within viral Env that ultimately leads to the fusion of the viral and cell membranes, completing the viral entry process. Using a combination of high-content pharmacophore in silico screening, chemical syntheses, bioisosteric replacement, and antiviral testing, we have developed a novel entry inhibitor, SC12, which inhibits the entry of HIV-1 into susceptible cells in the nanomolar range. Direct binding of SC12 to HIV-1 Env did not block Env interaction with the host cellular receptors, thereby allowing Env attachment to the host target cell. Additionally, differential scanning calorimetry indicates that interaction of SC12 with the soluble cleaved trimeric SOSIP.664 gp140 thermally stabilizes the protein. Moreover, binding of SC12 to HIV-1 Env did not alter recognition of epitopes on Env surface by broadly neutralizing and non-neutralizing antibodies. Furthermore, SC12-induced resistance mutations were located away from the CD4-binding site. Envs from SC12-resistant viruses have conformations closely resembling the post-engagement "prefusogenic" state exposing the conserved MPER region, therefore, making these viruses more susceptible to neutralization by MPER-specific antibodies. Taken together, SC12 functions as a novel allosteric HIV-1 fusion inhibitor, binding to Env and preventing conformational changes downstream of receptor engagement that lead to viral and cell membrane fusion.
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Details
- Title
- Investigation into the mechanism of a novel HIV-1 fusion inhibitor, SC12
- Creators
- Marina Tuyishime - DU
- Contributors
- Simon Cocklin (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 7177; 991014632701704721