Targeting extracellular and membrane proteins for degradation via lysosome targeting chimeras
Abstract/Contents
- Abstract
- Targeted protein degradation (TPD) is a promising strategy to remove deleterious proteins for therapeutic benefit and to probe biological pathways. The past two decades has witnessed a surge in development of technologies that rely on intracellular machinery to degrade challenging cytosolic targets. However, these TPD platforms leave the majority of extracellular and membrane proteins untouched. To enable degradation of these classes of proteins, we developed lysosome targeting chimeras (LYTACs) as a general strategy to degrade both secreted and membrane-anchored targets as introduced in Chapter 1. The first lysosome targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the lysosome trafficking receptor, cation-independent mannose-6-phosphate receptor (CI-M6PR). Because CI-M6PR has broad tissue distribution, harnessing a receptor with tissue-restricted expression could mitigate off-target effects and allow tissue-specific degradation. In Chapter 2, we developed "GalNAc-LYTACs" that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosomal targeting receptor, to degrade extracellular proteins in a cell type-specific manner. Site-specific conjugation and development of homogeneous LYTAC ligands improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs represent an avenue for cell-type restricted protein degradation, and additional discovery of recycling receptors with distinct and exclusive localization would expand the range of tissues or cells that LYTACs can target with selectivity. To address this need, we generated a comprehensive map of receptors that traffic from the plasma membrane to the lysosome across different tissues in mice in Chapter 3. Although extracellular degrader technologies have recently expanded the scope of potential therapeutic targets, no prior work has identified cellular features which enable or inhibit membrane protein degradation. Development of LYTACs as therapeutics would greatly benefit from insight into the factors that govern their activity. In Chapter 4, we conducted a genome-wide CRISPR screen to identify modulators of LYTAC-mediated membrane protein degradation. Our findings inform new design strategies for LYTACs with enhanced degradation activity and elucidate fundamental insights of receptor occupancy and trafficking.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Ahn, Green |
|---|---|
| Degree supervisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Long, Jonathan Z |
| Degree committee member | Du Bois, Justin |
| Degree committee member | Long, Jonathan Z |
| Associated with | Stanford University, School of Humanities and Sciences |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Green Ahn. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/sd354ck8170 |
Access conditions
- Copyright
- © 2023 by Green Ahn
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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