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Crafting Attractive Non-Covalent Interactions for the Study of β-Hairpins with Long Loops
- Date Issued:
- 2023
- Abstract/Description:
- In this study, we developed a new peptide motif called β-strap (strap = strand + cap) used to fold β-hairpins of varying length. β-Straps are mean to be short sequences (4 to 8 a-amino acids) forming β-sheets using a judicious combination of non-covalent interactions (NCI) to overcome the entropic penalty inherent to long loop closure. Among those, we proved that a couple of CH-π / NH-π interactions from a tryptophan zipper motif were critical to create a stable packing of the structure. To optimize these interactions, we incorporated unnatural tryptophan derivatives having functionalized indole side chains. Finally, the innate ability of the β-strap to bring β-stand in close contact was exploited to promote macrocyclization of long coiled peptides (up to 16 residues). Then, we studied a more complex β-hairpin loop mimics found at the apex of monoclonal antibodies (mAb) complementary determining region 3 (CDR-H3). Using a set of bioinformatics tools, a search of PDB crystal structures revealed that a large set of mAb crystals possess a β-bulge, located at the edge of CDR-H3 loops. A cluster analysis revealed it has an impressive adaptability towards different H3-loop sizes and conformations. In order to evaluate its function in antibodies, we synthesized several β-hairpin models bearing a prototypical β-bulge. By combining short β-straps and the β-bulge, we were able to design β-hairpin peptides mimic of mAb with a variety of lengths and rigidity while retaining a high degree of folding. Starting from pembrolizumab, the most outstanding blocker of the PD-1/PD-L1 checkpoint currently available in clinic, we scoped ~30 CDR-H3 mAb mimics (H3 loop). As a result, several novel β-hairpin peptide inhibitors of the PD-1/PD-L1 pathway were identified (IC50 <0.3 μM).
Title: | Crafting Attractive Non-Covalent Interactions for the Study of β-Hairpins with Long Loops. |
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Name(s): |
Richaud, Alexis D. , author Roche, Stéphane P. , 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: | 408 p. | |
Language(s): | English | |
Abstract/Description: | In this study, we developed a new peptide motif called β-strap (strap = strand + cap) used to fold β-hairpins of varying length. β-Straps are mean to be short sequences (4 to 8 a-amino acids) forming β-sheets using a judicious combination of non-covalent interactions (NCI) to overcome the entropic penalty inherent to long loop closure. Among those, we proved that a couple of CH-π / NH-π interactions from a tryptophan zipper motif were critical to create a stable packing of the structure. To optimize these interactions, we incorporated unnatural tryptophan derivatives having functionalized indole side chains. Finally, the innate ability of the β-strap to bring β-stand in close contact was exploited to promote macrocyclization of long coiled peptides (up to 16 residues). Then, we studied a more complex β-hairpin loop mimics found at the apex of monoclonal antibodies (mAb) complementary determining region 3 (CDR-H3). Using a set of bioinformatics tools, a search of PDB crystal structures revealed that a large set of mAb crystals possess a β-bulge, located at the edge of CDR-H3 loops. A cluster analysis revealed it has an impressive adaptability towards different H3-loop sizes and conformations. In order to evaluate its function in antibodies, we synthesized several β-hairpin models bearing a prototypical β-bulge. By combining short β-straps and the β-bulge, we were able to design β-hairpin peptides mimic of mAb with a variety of lengths and rigidity while retaining a high degree of folding. Starting from pembrolizumab, the most outstanding blocker of the PD-1/PD-L1 checkpoint currently available in clinic, we scoped ~30 CDR-H3 mAb mimics (H3 loop). As a result, several novel β-hairpin peptide inhibitors of the PD-1/PD-L1 pathway were identified (IC50 <0.3 μM). | |
Identifier: | FA00014154 (IID) | |
Degree granted: | Dissertation (PhD)--Florida Atlantic University, 2023. | |
Collection: | FAU Electronic Theses and Dissertations Collection | |
Note(s): | Includes bibliography. | |
Subject(s): |
Antibodies Peptides Biochemistry β-Hairpins |
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Persistent Link to This Record: | http://purl.flvc.org/fau/fd/FA00014154 | |
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. | |
Use and Reproduction: | http://rightsstatements.org/vocab/InC/1.0/ | |
Host Institution: | FAU | |
Is Part of Series: | Florida Atlantic University Digital Library Collections. |