Branched peptide-based targeted protein degraders for the modulation of ternary complex geometry
| dc.contributor.author | Almonte, Joshua | |
| dc.contributor.chair | Alabi, Christopher | en_US |
| dc.contributor.committeeMember | DeLisa, Matthew | en_US |
| dc.date.accessioned | 2025-06-30T20:37:06Z | |
| dc.date.available | 2025-06-30T20:37:06Z | |
| dc.date.issued | 2024-12 | |
| dc.description | 65 pages | en_US |
| dc.description.abstract | Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional targeted protein degraders that selectively degrade a protein of interest (POI) by recruiting innate protein degradation machinery. The current PROTAC design landscape is limited by the use of small molecules as ligands which are difficult to design and modify and have a limited range of potential targets. Peptide-based PROTACs (PepTACs) address these limitations through their modularity, standardized synthesis, and the availability of tools—such as phage display, yeast display, and increasingly powerful computational techniques—for designing peptide ligands against nearly any protein target. Here, we aim to expand on the design of PepTACs by proposing a method to modify the linker attachment point utilizing selectively branched, peptide ligands and solid-phase peptide synthesis. As a proof-of-concept, two model branched PepTACs were synthesized and characterized against the oncoprotein known as Cell Cycle-Related and Expression-Elevated Protein in Tumor (CREPT). Lipid nanoparticle delivery of PepTACs was explored, revealing peptide hydrophobicity as a driving force for encapsulation. LNP delivery of the branched constructs into HeLa cells showed dose-dependent cellular uptake. However, a CREPT-luciferase degradation assay yielded inconclusive results regarding their intracellular activity. Circular dichroism indicates branching destabilizes central binding features. Further studies are needed to elucidate the structure-activity relationships of branched PepTACs. | en_US |
| dc.identifier.doi | http://doi.org/10.7298/gc6r-1t23 | |
| dc.identifier.other | Almonte_cornell_0058O_12145 | |
| dc.identifier.other | http://dissertations.umi.com/cornell:12145 | |
| dc.identifier.uri | https://hdl.handle.net/1813/117110 | |
| dc.language.iso | en | |
| dc.subject | Peptide | en_US |
| dc.subject | PROTAC | en_US |
| dc.subject | Ternary Complex | en_US |
| dc.title | Branched peptide-based targeted protein degraders for the modulation of ternary complex geometry | en_US |
| dc.type | dissertation or thesis | en_US |
| dcterms.license | https://hdl.handle.net/1813/59810.2 | |
| thesis.degree.discipline | Chemical Engineering | |
| thesis.degree.grantor | Cornell University | |
| thesis.degree.level | Master of Science | |
| thesis.degree.name | M.S., Chemical Engineering |
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