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Thesis
Exploring the functionality of novel small molecule DAVEIs on HIV-1
Master of Science (M.S.), Drexel University
Jun 2019
DOI:
https://doi.org/10.17918/mr1v-qn82
Abstract
Although there have been many gains made in the fight against HIV it remains a global health crisis. Drug and vaccine development have focused on targeting the HIV envelope proteins (Env) for they are expressed across all strains of virus and thus can be broadly neutralizing. The Chaiken lab has recently developed a new type of Env targeting molecule called the dual acting virucidal entry inhibitor (DAVEI). The DAVEI molecule was originally a recombinant chimera comprised of the gp120 targeting protein cyanovirin-N (CVN) linked via a peptide linker to the gp41 targeting peptide sequence termed MPER. The exact mechanism of DAVEI lysis is currently unknown, however the prevailing theory suggests the dual binding of the CVN and MPER to gp120 and gp41 respectively leads to a tension that disrupts the stability of the membrane causing lysis. In order to determine the potential for a more translatable DAVEI, a new small molecule was synthetically engineered. This was done by first replacing the warhead CVN protein with the previously established gp120 binding cyclic peptide AAR029b (29b). Second, the MPER peptide was replaced with the MPER truncated peptide Trp3 and finally the linker was changed to a polyethylene glycol (PEG) polymer. This molecule was synthesized using solid phase peptide synthesis and characterized for lysis using a p24 sandwich ELISA, for antiviral activity using a luciferase based antiviral assay, and for gp120 binding activity via a 17b competition ELISA. Characterization of the small molecule DAVEI design showed first that it was able to induce viral lysis however with a weak potency. Second, it was shown that the small molecule DAVEI was able to demonstrate antiviral activity however with a weaker potency than the warhead group alone. Finally, it was shown that the small molecule DAVEI bound monomeric Yu2 gp120 with a lower affinity than the warhead group alone. The observed DAVEI lytic, antiviral, and gp120 binding characterization demonstrated that these mechanisms of action are translatable to smaller peptidic components. Although the small molecule DAVEI design lacked efficacy in the areas of examination, it has set the groundwork for future development of a more translatable designs.
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Details
- Title
- Exploring the functionality of novel small molecule DAVEIs on HIV-1
- Creators
- Harry Bach - DU
- Contributors
- Irwin Chaiken (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 43 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 9439; 991014632535704721