Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome

Abstract

Snyder Robinson Syndrome (SRS) is a rare disease associated with a defective spermine synthase gene and low intracellular spermine levels. In this study, a spermine replacement therapy was developed using a spermine prodrug that enters cells via the polyamine transport system. The prodrug was comprised of three components: a redox-sensitive quinone “trigger”, a “trimethyl lock (TML)” aryl “release mechanism”, and spermine. The presence of spermine in the design facilitated uptake by the polyamine transport system. The quinone–TML motifs provided a redox-sensitive agent, which upon intracellular reduction generated a hydroquinone, which underwent intramolecular cyclization to release free spermine and a lactone byproduct. Rewardingly, most SRS fibroblasts treated with the prodrug revealed a significant increase in intracellular spermine. Administering the spermine prodrug through feeding in a Drosophila model of SRS showed significant beneficial effects. In summary, a spermine prodrug is developed and provides a lead compound for future spermine replacement therapy experiments.

METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification

“…The results showed that the spermine level was significantly increased in cells overexpressing SMS, while after knocking down SMS, the spermidine level was significantly accumulated ( Figures 3A, B ). It is noteworthy that similar results of spermidine buildup have been seen in the fibroblasts of patients with Snyder Robinson Syndrome which have defective SMS ( 29 ). To further verify the relationship between SMS and AKT , western blot analysis was performed and showed that over-expression of SMS can up-regulate the level of p-AKT while knocking down SMS can reduce the expression of p-AKT ( Figure 3C ).…”

“…It should be realized that SMS may also directly act on other oncogenes through protein-protein interactions. There are three domains in SMS protein ( 29 , 30 ). By searching The Molecular INTeraction Database (MINT database), we found some proteins that may interact with SMS proteins, including IMMP2L, MAPK6, MAPKAPK3, MAPK8IP2, RPS6KA3.…”

X‐Linked intellectual disability update 2022

“…Gene therapy and mRNA therapy are in preclinical trials for fragile X and Rett syndrome but neither is available for clinical use (Hooper et al, 2021; Katz et al, 2012). A prodrug has been recently developed for Snyder‐Robinson syndrome (Tantak et al, 2021). Identification of the causes of XLID, however, have allowed prevention methods (carrier testing, prenatal diagnosis, preimplantation genetics, donor gametes) to be used by couples at risk of recurrence in their offspring.…”

Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells

“…Antioxidant treatment, such as the ROS scavenger AD4, partially restores mitochondrial function but not lysosomal function in the Drosophila model ( 22 ). Certain polyamine analogs also show some benefit in rebalancing the spermidine/spermine ratio in cell lines and disease models ( 28 , 29 ). Efforts to rebalance the spermidine/spermine ratio by direct spermine supplementation in vivo have not been beneficial ( 28 – 30 ).…”

“…Certain polyamine analogs also show some benefit in rebalancing the spermidine/ spermine ratio in cell lines and disease models (28,29). Efforts to rebalance the spermidine/spermine ratio by direct spermine supplementation in vivo have not been beneficial (28)(29)(30).…”