Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy.
Hawley BrownMia ChungAlina ÜffingNefeli BatistatouTiffany TsangSamantha DoskocilWeiqun MaoDieter WillboldRobert C BastZhen LuOliver H WeiergräberJoshua A KritzerPublished in: Journal of the American Chemical Society (2022)
The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized ovarian cancer cells to cisplatin. These small, potent stapled peptides represent promising autophagy-modulating compounds that can be developed as novel cancer therapeutics and novel mediators of targeted protein degradation.
Keyphrases
- cell death
- signaling pathway
- endoplasmic reticulum stress
- amino acid
- oxidative stress
- simultaneous determination
- small molecule
- mass spectrometry
- liquid chromatography
- squamous cell carcinoma
- drug delivery
- single molecule
- radiation therapy
- circulating tumor
- young adults
- tandem mass spectrometry
- childhood cancer
- squamous cell
- chemotherapy induced