Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy

被引:24
作者
Brown, Hawley [1 ]
Chung, Mia [1 ]
Ueffing, Alina [2 ,3 ]
Batistatou, Nefeli [1 ]
Tsang, Tiffany [1 ]
Doskocil, Samantha [4 ]
Mao, Weiqun [4 ]
Willbold, Dieter [2 ,3 ]
Bast, Robert C., Jr. [4 ]
Lu, Zhen [4 ]
Weiergraeber, Oliver H. [2 ]
Kritzer, Joshua A. [1 ]
机构
[1] Tufts Univ, Dept Chem, Medford, MA 02155 USA
[2] Forschungszentrum Julich, Inst Biol Informat Proc, Struct Biochem IBI 7, D-52425 Julich, Germany
[3] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, D-40225 Dusseldorf, Germany
[4] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
基金
美国国家科学基金会;
关键词
PROMOTES GROWTH; MOTIF;
D O I
10.1021/jacs.2c04699
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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.
引用
收藏
页码:14687 / 14697
页数:11
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