Investigating Mimetics of a Peptide Derived from the Effector Domain of MARCKS as Possible Therapeutics for Spinal Cord Injury

Abstract

Like other conditions affecting the central nervous system, spinal cord injury (SCI) is difficult to treat with molecular therapies because the blood-brain barrier makes intravenous treatments largely ineffective. For example, a synthetic peptide chain derived from the effector domain (ED) of myristoylated alanine-rich C-kinase substrate (MARCKS) has been found to improve functional recovery after SCI in female mice; however, peptides do not always pass the blood-brain barrier and are easily degraded due to natural proteases and are excreted during kidney filtration. Therefore, the ED peptide cannot access the central nervous system to exhibit its effects if administered intravenously. Instead of injecting the ED peptide into the bloodstream, we propose to find compounds that can pass the blood-brain barrier in place of the ED peptide, improving treatment compatibility. To find such alternatives, we screened compound libraries via competitive enzyme-linked immunosorbent assay (ELISA) and identified five potential ED peptide mimetics—compounds that mimic the structure and function of the ED peptide. We then used another competitive ELISA to verify their structural similarity to the peptide. After performing toxicity tests to determine the appropriate concentrations of the mimetics to use in functional assays, we found that all five mimetics trigger a significant increase in neurite length in neurons from female mice, but not male mice, when compared to the vehicle control solution. Although more functional tests are necessary, these results suggest that these mimetics trigger ED peptide functions and may provide a more efficient treatment alternative for SCI.