Amyotrophic lateral sclerosis (ALS) is a lethal, rapidly spreading neurodegenerative disease targeting motor neurons of the brain and spinal cord, causing patients pain, depression, and paralysis. In one of the most prevalent forms of the disease, dipeptide repeats (DPRs) that are toxic to motor neuron cells are produced due to a genetic mutation. We aim to utilize enantiomeric biomaterials to sequester and clear these toxic DPRs, and thereby slow or halt disease progression. Mixtures of enantiomeric peptides, <i>i.e.</i>, stereocomplexes, have been shown to result in blends with enhanced material properties relative to the individual component peptides (<i>e.g.</i> yielding fibers with four times greater moduli than individual component fibers and protease-resistant hydrogels) due to strong peptide-peptide noncovalent bonds. Inspired by these results, we investigate the differences in interaction affinity between DPRs with the same and complementary stereochemical configurations. ALS-relevant D- and L-DPRs were prepared by microwave-assisted solid phase peptide synthesis methods and purified by preparative-scale high performance liquid chromatography (HPLC); characterization shows that synthetic DPRs recapture native DPR structure. We perform isothermal titration calorimetry measurements to determine enthalpy of binding and binding affinity, comparing L- and L-DPRs to D- and L-DPRs. Preliminary binding data for D- and L-DPRs show an approximately 5-fold increase in binding enthalpy over L- and L-DPRs. These results support the hypothesis that enantiomeric peptide complexes have higher binding affinity than individual component peptide complexes. Ongoing binding affinity studies modulating factors of length and sequence mismatches, informing the design of a toxic DPR sequestration system, where D-DPRs conjugated to a biocompatible polymer will bind toxic L-DPRs and yield therapeutic outcomes.

Utilizing interactions between enantiomeric peptides to sequester toxic dipeptide repeats for treatment of amyotrophic lateral sclerosis

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.