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Discovery of GPX4 inhibitory peptides from random peptide T7 phage display and subsequent structural analysis
Kotaro Sakamoto1, Satoshi Sogabe1, Yusuke Kamada1
1Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
Abstract:
The phospholipid hydroperoxidase glutathione peroxidase (GPX4) is an enzyme that reduces lipid hydroperoxides in lipid membranes. Recently, GPX4 has been investigated as a target molecule that induces iron-dependent cell death (ferroptosis) selectively in cancer cells that express mutant Ras. GPX4 inhibitors have the potential to become novel anti-cancer drugs. However, there are no druggable pockets for conventional small molecules on the molecular surface of GPX4. To generate GPX4 inhibitors, we examined the use of peptides as an alternative to small molecules. By screening peptide libraries displayed on T7 phages, and analyzing the X-ray crystal structures of the peptides, we successfully identified one peptide that binds to near Sec73 of catalytic site and two peptides that bind to another site on GPX4. To our knowledge, this is the first study reporting GPX4 inhibitory peptides and their structural information.
Insights
Researchers developed novel peptide inhibitors for GPX4, an enzyme targeted in cancer therapy. These peptides offer a new strategy for developing anti-cancer drugs, overcoming limitations of traditional small molecules.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Phospholipid hydroperoxidase glutathione peroxidase (GPX4) reduces lipid hydroperoxides.
- GPX4 is a target for inducing ferroptosis in Ras-mutant cancer cells.
- GPX4 inhibitors show potential as novel anti-cancer therapeutics.
Purpose of the Study:
- To explore peptides as an alternative to small molecules for GPX4 inhibition.
- To identify and structurally characterize GPX4-binding peptides.
- To overcome the lack of druggable pockets on GPX4 for small molecules.
Main Methods:
- Screening of T7 phage-displayed peptide libraries.
- X-ray crystallography for structural analysis of peptide-GPX4 interactions.
- Identification of peptides binding to specific sites on GPX4.
Main Results:
- Identified three novel GPX4-inhibitory peptides.
- Determined the binding sites of the identified peptides.
- One peptide binds near the Sec73 catalytic site; two bind to another distinct site.
Conclusions:
- This study reports the first GPX4-inhibitory peptides and their structural data.
- Peptides represent a promising alternative for targeting GPX4 in cancer therapy.
- Structural information provides a basis for further development of peptide-based GPX4 inhibitors.
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