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Published on: June 30, 2023
Stapled Peptide Inhibitors of Autophagy Adapter LC3B
Robert A Cerulli1, Livia Shehaj2, Hawley Brown2
1Cell, Molecular and Developmental Biology Program Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Abstract:
A growing body of evidence suggests that autophagy inhibition enhances the effectiveness of chemotherapy, especially in difficult-to-treat cancers. Existing autophagy inhibitors are primarily lysosomotropic agents. More specific autophagy inhibitors are highly sought-after. The microtubule-associated protein 1A/1B light chain 3B protein, LC3B, is an adapter protein that mediates key protein-protein interactions at several points in autophagy pathways. In this work, we used a known peptide ligand as a starting point to develop improved LC3B inhibitors. We obtained structure-activity relationships that quantify the binding contributions of peptide termini, individual charged residues, and hydrophobic interactions. Based on these data, we used artificial amino acids and diversity-oriented stapling to improve affinity and resistance to biological degradation, while maintaining or improving LC3B affinity and selectivity. These peptides represent the highest-affinity LC3B-selective ligands reported to date, and they will be useful tools for further elucidation of LC3B's role in autophagy and in cancer.
Insights
Developing novel autophagy inhibitors targeting LC3B protein can enhance chemotherapy effectiveness for hard-to-treat cancers. These new peptide inhibitors show high affinity and selectivity for LC3B, aiding cancer treatment research.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Autophagy inhibition enhances chemotherapy efficacy, particularly in challenging cancers.
- Current autophagy inhibitors are mainly lysosomotropic, highlighting the need for more specific agents.
- Microtubule-associated protein 1A/1B light chain 3B (LC3B) is crucial for autophagy pathway protein-protein interactions.
Purpose of the Study:
- To develop novel, high-affinity, and selective LC3B inhibitors.
- To improve upon existing peptide ligands for LC3B inhibition.
- To create tools for investigating LC3B's role in autophagy and cancer.
Main Methods:
- Utilized a known peptide ligand as a scaffold for inhibitor development.
- Determined structure-activity relationships (SAR) for peptide termini, charged residues, and hydrophobic interactions.
- Employed artificial amino acids and diversity-oriented stapling to enhance peptide properties.
Main Results:
- Quantified binding contributions of various peptide modifications.
- Developed peptides with improved affinity and resistance to biological degradation.
- Achieved enhanced LC3B affinity and selectivity compared to previous ligands.
Conclusions:
- The novel peptides represent the highest-affinity LC3B-selective ligands reported.
- These inhibitors are valuable tools for studying autophagy and its role in cancer.
- Further research can leverage these inhibitors to explore therapeutic strategies.
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