Hydrogen sulfide (H2S) is a gasotransmitter that is produced endogenously and freely permeates cell membranes. It plays important roles in many physiological pathways, and by regulating these pathways, it provides many therapeutic effects. For example, H2S dilates vascular vessels, promotes angiogenesis, and protects cells from oxidative stress. Due to its therapeutic effects, H2S has been used as a potential treatment for diseases like diabetes, ischemia-reperfusion injuries, lung diseases, ulcers and edemas, among others. To apply H2S for therapeutic applications, two challenges need to be addressed. The first challenge is the H2S donor, which not only provides H2S but must be stable enough to avoid side effects caused by overdose; and the second challenge is the delivery strategies, which transport the H2S to the target sites.
A series of S-aroylthiooximes (SATOs), an H2S releasing compound, were synthesized and conjugated to peptide sequences to form H2S-releasing aromatic peptide amphiphile (APA) hydrogels. APAs formed nanofibers, which were stabilized by beta-sheets and aromatic stacking. The self-assembled structures were affected by the substituents on the aromatic rings of SATOs, leading to the formation of twisted nanofibers. After the addition of cysteine, H2S was released from the APAs with half-lives ranging from 13 min to 31 min. The electron-donating groups slowed down the H2S release rate, while the electron-withdrawing groups accelerated the release rate. Therefore, the release rates of H2S were controlled by electronic effects. When self-assembled structures were formed, the H2S release rate was slowed down even more, due to the difficulties in cysteine diffusion into the core of the structures.
Antimicrobial effects were also discovered using the H2S releasing APA hydrogels. The H2S-releasing dipeptides S-FE and S-YE formed self-assembled twisted nanoribbons and nanotubes, respectively. The non H2S-releasing control oxime dipeptides C-FE and C-YE were also synthesized. The C-FE formed nanoribbons while the C-YE only showed non-specific aggregates. S-FE and S-YE released H2S with peaking times of about 41 and 39 min. Both the self-assembled structures and the release rates were affected by their packing differences. In vitro and ex vivo experiments with Staphylococcus aureus (Xen29), a commonly found bacterium on burn wounds, showed significant antimicrobial effects. APAs S-FE and C-FE eliminated Xen29 and inhibited the biofilm formation, while S-FE always showed better effects than C-FE. These antimicrobial H2S-releasing APA hydrogels provide a new approach to treat burn wound infections, and provide healing benefits due to the therapeutic effects of H2S. / Doctor of Philosophy / Hydrogen sulfide (H₂S) is a signaling gas that produced in our body. It regulates physiological pathways, and can be a potential treatment for diseases like diabetes, ischemia-reperfusion injuries, lung diseases, ulcers and edemas, among others. However, two issues need to be addressed before applying H₂S for disease treatments. The first issue is to choose an H₂S donor, which is stable enough to avoid side effects caused by overdose. The second issue is the delivery methods, which transport the H₂S to target sites.
A series of S-aroylthiooximes (SATOs), an H₂S releasing compound, were synthesized and attached to peptide sequences to form H₂S-releasing self-assembled aromatic peptide amphiphile (APA) hydrogels. The APA hydrogels were found to be affected by the substituents on the SATO structures. For example, the H₂S released from APAs had halflives ranged from 13 min to 31 min, which were controlled by the substituents. When hydrogels were formed, the H₂S release was slowed down even more, due to the difficulties in cysteine diffusion into the SATO structures.
The antimicrobial effects were also discovered using the H₂S releasing APA hydrogels. Two H₂S-releasing APA hydrogels, S-FE and S-YE, were formed. At the same time, two non H₂S-releasing oxime dipeptides, C-FE and C-YE, were also synthesized as controls. The H₂S-releasing peptides, S-FE and S-YE, released H₂S with peaking times of about 41 and 39 min, while no H₂S was released from C-FE and C-YE. The self-assembled structures and the release rates were affected by their structural differences. In vitro and ex vivo experiments with Staphylococcus aureus (Xen29), a commonly found bacterium on burn wound, showed significant antimicrobial effects. Both H₂S-releasing S-FE and non H₂S-releasing C-FE eliminated Xen29 and inhibited the biofilm formation, indicating the potential use of the designed peptides as antimicrobial treatment for wounds. The S-FE always showed better effects than C-FE, suggesting the benefit of H₂S during the elimination of bacteria. These antimicrobial H₂S-releasing APA hydrogels provide a new approach to treat burn wound infection and provide healing benefits due to the therapeutic effects of H₂S.
Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/101094 |
Date | 21 June 2019 |
Creators | Qian, Yun |
Contributors | Chemistry, Matson, John B., Whittington, Abby R., Barone, Justin R., Edgar, Kevin J., Davis, Richey M. |
Publisher | Virginia Tech |
Source Sets | Virginia Tech Theses and Dissertation |
Detected Language | English |
Type | Dissertation |
Format | ETD, application/pdf, application/pdf |
Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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