Chemoproteomic Identification of Spermidine-Binding Proteins and Antitumor-Immunity Activators
Vaibhav Pal Singh1,2, Shuhei Hirose3, Misao Takemoto1
1Division of Biochemistry, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
Abstract:
Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity. Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO). Herein, we report a spermidine-based chemoproteomic probe (probe 2) that enables profiling of spermidine-binding proteins and screening for small-molecule enhancers of mitochondrial FAO. Chemoproteomic profiling by the probe revealed 140 proteins engaged in cellular interaction with spermidine, with a significant majority being mitochondrial proteins. Hydroxyl coenzyme A (CoA) dehydrogenase subunits α (HADHA) and other lipid metabolism-linked proteins are among the mitochondrial proteins that have attracted considerable interest. Screening spermidine analogs with the probe led to the discovery of compound 13, which interacts with these lipid metabolism-linked proteins and activates HADHA. This simple and biostable synthetic compound we named "spermimic" mirrors spermidine's ability to enhance mitochondrial bioenergetics and displays similar effectiveness in augmenting PD-1 blockade therapy in mice. This study lays the foundation for developing small-molecule activators of antitumor immunity, offering potential in combination cancer immunotherapy.
Insights
Aging impairs cancer immunotherapy. Spermidine enhances antitumor immunity by boosting mitochondrial fatty acid oxidation. A new compound, spermimic, mimics spermidine
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Cancer immune therapies, like PD-1 blockade, are less effective in older adults due to weakened T-cell immunity.
- Spermidine, a natural compound that decreases with age, can potentially restore antitumor immunity by improving mitochondrial fatty acid oxidation (FAO).
Purpose of the Study:
- To develop a chemoproteomic probe for identifying spermidine-binding proteins and screening for compounds that enhance mitochondrial FAO.
- To discover novel small molecules that can boost antitumor immunity and improve cancer immunotherapy outcomes in aging populations.
Main Methods:
- A novel spermidine-based chemoproteomic probe (probe 2) was synthesized and utilized.
- Chemoproteomic profiling identified spermidine-interacting proteins, with a focus on mitochondrial proteins involved in lipid metabolism.
- High-throughput screening of spermidine analogs using the probe led to the discovery of a potent enhancer of mitochondrial FAO.
Main Results:
- The probe identified 140 spermidine-binding proteins, predominantly mitochondrial, including HADHA and other lipid metabolism-related proteins.
- A novel compound, termed "spermimic" (compound 13), was discovered, which activates HADHA and enhances mitochondrial bioenergetics.
- Spermimic demonstrated efficacy comparable to spermidine in improving PD-1 blockade therapy in mouse models.
Conclusions:
- This study introduces a valuable chemoproteomic tool for studying spermidine's role in cellular processes.
- Spermimic represents a promising small-molecule activator of antitumor immunity with potential for combination cancer immunotherapy.
- The findings pave the way for developing new therapeutic strategies to overcome age-related decline in cancer immunotherapy effectiveness.
