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Synthesis and Biological Evaluation of β-hairpin Peptides as Covalent Inhibitors of the PD-1/PD-L1 Immune Checkpoint
| Title: | Synthesis and Biological Evaluation of β-hairpin Peptides as Covalent Inhibitors of the PD-1/PD-L1 Immune Checkpoint. |
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| Name(s): |
Naylon, Sarah , author Roche, Stephane, Thesis advisor Florida Atlantic University, Degree grantor Department of Chemistry and Biochemistry Charles E. Schmidt College of Science |
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| Type of Resource: | text | |
| Genre: | Electronic Thesis Or Dissertation | |
| Date Created: | 2023 | |
| Date Issued: | 2023 | |
| Publisher: | Florida Atlantic University | |
| Place of Publication: | Boca Raton, Fla. | |
| Physical Form: | application/pdf | |
| Extent: | 135 p. | |
| Language(s): | English | |
| Abstract/Description: | Protein─protein interactions (PPIs) are essential for cell─cell interactions and cellular signal transduction, which play a crucial role in various human diseases. PPIs involved in cancer immunology pathways, known as immune checkpoints, have been intensely studied, leading to a new approach to cancer therapy. The PD1:PDL1 interaction is one of the most essential immune checkpoints. Studies on PD1:PDL1 showed over ten clinical monoclonal antibodies (mAb) used to treat cancer patients. Unfortunately, antibodies do not penetrate the tumor microenvironment well, and clearance from the body is slow, leading to unwanted side effects. There is a significant gap in the drug market between the typical Rule of 5 (Ro5) small-molecule drugs (MW<0.5 kDa, SASA ~150 Å) and large antibodies with molecular weights greater than 40 kDa (SASA >2,000 Å). PPIs remain challenging to modulate by small molecules due to their large, shallow, often dynamic, and water-exposed surfaces lacking well-defined binding pockets. Thus, our lab was drawn to work on large β-hairpin peptides (2-3 kDa) that can potentially mimic the CDR-H3 loops of some of the most potent and clinical anti-PD1 antibodies. Exploration of these β-hairpin peptides provided valuable insights into their folding stability, conformational flexibility, passive membrane permeability, and protein-protein interaction (PPI) blocking activities. Additionally, the rational design of TCIs against PD1, specifically targeting a lysine residue, emerged as a strategy to irreversibly obstruct the PD1:PDL1 protein-protein interaction enhancing potency of the non-covalent inhibitors by taking advantage of their specificity. Meticulous structural analysis, peptide synthesis, and biological evaluations are presented contributing comprehensions into covalent inhibitor development of drugs fbRo5. | |
| Identifier: | FA00014353 (IID) | |
| Degree granted: | Thesis (MS)--Florida Atlantic University, 2023. | |
| Collection: | FAU Electronic Theses and Dissertations Collection | |
| Note(s): | Includes bibliography. | |
| Subject(s): |
Cancer--Immunological aspects Protein-protein interactions Antibodies, Monoclonal |
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| Persistent Link to This Record: | http://purl.flvc.org/fau/fd/FA00014353 | |
| Use and Reproduction: | Copyright © is held by the author with permission granted to Florida Atlantic University to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder. | |
| Host Institution: | FAU |
