bims-polyam 2024-06-09 papers

Issue of 2024–06–09
two papers selected by
Sebastian J. Hofer, University of Graz

J Am Chem Soc. 2024 Jun 07.

Chemoproteomic Identification of Spermidine-Binding Proteins and Antitumor-Immunity Activators.

Vaibhav Pal Singh, Shuhei Hirose, Misao Takemoto, Asmaa M A S Farrag, Shin-Ichi Sato, Tasuku Honjo, Kenji Chamoto, Motonari Uesugi.

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.

DOI: https://doi.org/10.1021/jacs.3c14615

Int J Biol Macromol. 2024 Jun 03. pii: S0141-8130(24)03686-9. [Epub ahead of print] 132881

Attenuating intervertebral disc degeneration through spermidine-delivery nanoplatform based on polydopamine for persistent regulation of oxidative stress.

Dongliang Wang, Kun Lu, Guoyou Zou, Duanrong Wu, Yi Cheng, Yongming Sun.

As one of the most widespread musculoskeletal diseases worldwide, intervertebral disc degeneration (IVDD) remains an intractable clinical problem. Currently, oxidative stress has been widely considered as a significant risk factor in the IVDD pathological changes, and targeting oxidative stress injury to improve the harsh microenvironment may provide a novel and promising strategy for disc repair. It is evident that spermidine (SPD) has the ability to attenuate oxidative stress across several disease models. However, limited research exists regarding its impact on oxidative stress within the intervertebral disc. Moreover, enhancing the local utilization rate of SPD holds great significance in IVDD management. This study aimed to develop an intelligent biodegradable mesoporous polydopamine (PDA) nanoplatform for sustained release of SPD. The obtained PDA nanoparticles with spherical morphology and mesoporous structure released loaded-therapeutic molecules under low pH and H2O2. Combined treatment with SPD loaded into PDA nanoparticles (SPD/PDA) resulted in better therapeutic potential than those with SPD alone on oxidative stress injury. Furthermore, both SPD and SPD/PDA could induce anti-inflammatory M2 macrophage polarization. Upon injection into degenerative IVDs, the SPD/PDA group achieved a good repair efficacy with a long-term therapeutic effect. These findings indicated that the synergized use of SPD with responsive drug delivery nanocarriers may steadily scavenge reactive oxygen species and provide an effective approach toward the treatment of IVDD.

Keywords: Intervertebral disc degeneration; Mesoporous polydopamine nanoparticles; Oxidative stress; Regeneration; Spermidine

DOI: https://doi.org/10.1016/j.ijbiomac.2024.132881