eIF2 (eukaryotic initiation factor 2), an eukaryotic initiation factor, is an essential factor for protein synthesis. eIF2 mediates the binding of tRNA_i^Met to the ribosome in a GTP-dependent manner. And then it would be released from the ribosome bound to GDP as an inactive binary complex after the initiation phases completing. This factor consists of 3 subunits: α, β, γ. Among them, eIF2α phosphorylation (p-eIF2α) causes inhibition of global translation. Moreover, the p-eIF2α can conserve energy and facilitates the reprogramming of gene expression and signaling pathways that help to restore protein homeostasis. But, p-eIF2α is also the central component of the integrated stress response (ISR), which impairs long-term memory formation in rodents and birds. Therefore, eIF2α dephosphorylation has become a target for anti-inflammation.

Salubrinal is a cell-permeable and selective inhibitor of eIF2α dephosphorylation.

From: Alsterda A, et al. Front Oncol. 2021;11:654940.

Salubrinal acts as a dual-specificity phosphatase 2 (Dusp2) inhibitor and suppresses inflammation in anti-collagen antibody-induced arthritis. It also has antiviral activity against HSV-1 and inhibits dephosphorylation of eIF2α mediated by the HSV-1 protein ICP34.5.

Following the experiments in vitro, it is capable to protect against endoplasmic reticulum (ER) stress in various model systems. Salubrinal also strongly synergized with proteasome inhibitors to augment apoptotic death of different leukemic cell lines. Salubrinal preferentially seems to target the PP1/GADD34 complex.

Besides, in vivo, Salubrinal significantly suppresses inflammation of the paws of collagen antibody-induced arthritis (CAIA) mice. For instance, the clinical scores are 1.94±1.7 (placebo) and 0.31±0.6 (Salubrinal) on day 6, and 4.63±3.4 (placebo) and 1.09±1.6 (Salubrinal) on day 12. Consistent with the clinical scores, the thickening of the paws is also reduced in the Salubrinal-treated group. Furthermore, Salubrinal reduces the histological scores from 1.47±1.10 (N=16, placebo) to 0.59±0.64 (N=16, Salubrinal) (p=0.01).

In conclusion, Salubrinal is a potent inhibitor of eIF2α dephosphorylation that has the potential to research anti-inflammation.

References:

1. Sharma V, et al. Nature. 2020 Oct;586(7829):412-416.
2. Drexler HC. PLoS One. 2009;4(1):e4161.
3. Hamamura K, et al. Cell Signal. 2015 Apr;27(4):828-35.