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

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.