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Dissertation
Entry inhibitors targeting HIV-1 Env gp120 as AIDS microbicide candidates
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2011
DOI:
https://doi.org/10.17918/00009253
Abstract
Topical microbicides that can be used to prevent the spread of HIV-1 are urgently needed by women in the developing world. A recent clinical study has demonstrated that specifically targeting the virus reduces the rate of infection although the development of resistance mutations remains an important issue. Novel drugs are needed that can inactivate or block the virus and that are not part of the normal treatment regiment for the disease. This has brought a new emphasis on compounds that can block the initial attachment and entry of the virus. Entry occurs when the viral glycoprotein gp120 interacts with CD4 and a co-receptor resulting in the fusion of the viral and host cell membranes. One interesting inhibitor lead that targets this process is 12p1, a small peptide that binds to gp120 and blocks its interaction with both CD4 and the co-receptor but with low efficacy. We used several strategies to improve the potency of 12p1 and assessed the most promising compound for breadth of inhibition and safety. We initially modified 12p1 by creating a recombinant protein with 12p1 fused to the C-terminal domain of the small gp120 targeting lectin, cyanovirin-N. The chimera retained the high affinity binding and antiviral potentcy of cyanovirin-N as well as the dual antagonism of the 12p1 domain. We also analyzed the potential of a high potency peptide triazole derivative of 12p1, HNG-156, to act as a microbicide candidate. We found that HNG-156 can neutralize HIV-1 from subtypes A, B, C and D with no detectable toxicity. It can be combined with tenofovir or other entry inhibitors and appears to act synergistically with cyanovirin-N and other sugar binding compounds. Overall, we have improved the potency of the parent 12p1 and demonstrated that a peptide triazole derivative can be used as a safe and effective microbicide candidate to stop HIV-1.
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Details
- Title
- Entry inhibitors targeting HIV-1 Env gp120 as AIDS microbicide candidates
- Creators
- Karyn McFadden
- Contributors
- Irwin Chaiken (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 151 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991021889075404721