Erzina, Dina (2021). Immunomodulatory Peptide Dendrimers Inspired from Glatiramer Acetate. (Thesis). Universität Bern, Bern
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Abstract
Glatiramer Acetate (GA) is a popular first-line treatment drug for relapsing remitting multiple sclerosis (RRMS), a chronic autoimmune disease of central nervous system. GA is a mixture of random copolymers with the average size distribution between 4-9 kDA. Although, GA has been present on the market for more than 24 years, an active epitope or a sequence were not identified. One of the major difficulties preventing the discovery of the most active components of the mixture is due to the complexity of its synthesis. With the aim of identifying a precisely defined alternative to GA, we designed a diverse library of peptide dendrimers, which differ in their molecular weight, charge, and amino acid ratio. The design was conducted using computational approach as well as manually to produce peptide dendrimers with different structural features. Having a diverse library of peptide dendrimers, we then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human primary monocytes. IL-1Ra is a natural inhibitor of IL-1β, a proinflammatory cytokine, which is one of the effects of GA on immune cells. Several of the largest dendrimers were as active as GA. In order to understand better the structure-activity relationship, we then created a library, consisting of the active dendrimers analogs. Activity of the active dendrimer was strongly influenced by variations in amino acid sequence and stereochemistry. Having a defined active sequence, we performed a detailed biological evaluation of the cytokine secretion and regulation of the surface markers. In result, the differentiation of monocytes towards an M2 (anti-inflammatory) state was observed in response on the treatment. The confocal imaging with the fluorescent labelled analogs pointed out the distribution of the dendrimers mostly on the membrane of the monocytes but not the one of leukocytes. Since the active peptide dendrimer did not show measurable cellular toxicity, and its exact sequence is perfectly defined, this compound might serve as a starting point to develop a new class of immunomodulatory analogs of GA.
| Item Type: | Thesis |
|---|---|
| Dissertation Type: | Single |
| Date of Defense: | 26 October 2021 |
| Subjects: | 500 Science > 540 Chemistry 500 Science > 570 Life sciences; biology |
| Institute / Center: | 08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
| Depositing User: | Hammer Igor |
| Date Deposited: | 06 Dec 2024 12:33 |
| Last Modified: | 06 Dec 2024 23:25 |
| URI: | https://boristheses.unibe.ch/id/eprint/5660 |
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