MRZ-99030 - A novel modulator of Aβ aggregation: I - Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer's disease, glaucoma and age-related macular degeneration (AMD)

Neuropharmacology. 2015 May;92:158-69. doi: 10.1016/j.neuropharm.2014.12.038. Epub 2015 Jan 26.

Abstract

Therapeutic approaches addressing β-amyloid1-42 (Aβ1-42) aggregation represent a promising neuroprotective strategy for the treatment of Alzheimer's disease, dry age-related macular degeneration (AMD) and glaucoma. MRZ-99030 is a dipeptide containing d-tryptophan and 2-amino-2-methylpropionic acid in clinical development for the topical treatment of glaucoma and AMD. MRZ-99030 is an Aβ aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric Aβ species. The present study confirmed that MRZ-99030 prevents the formation of oligomeric Aβ species using similar SDS-PAGE experiments. However, additional data from TR-FRET, DLS and AFM experiments revealed that MRZ-99030 does not directly prevent early protein/protein interactions between monomeric Aβ, but rather promotes the formation of large, non-amyloidogenic, amorphous Aβ aggregates and thereby reduces the amount of intermediate toxic soluble oligomeric Aβ species. The affinity of MRZ-99030 to Aβ1-42 determined by SPR was 28.4 nM but the ratio of compound to Aβ is also important: a 10-20 fold excess of MRZ-99030 over Aβ is probably required for effective modulation of protein/protein interactions. For example, in glaucoma, assuming a maximal Aβ concentration of 1-15 nM in the retina, up to 150 nM MRZ-99030 could be required at the protein target. In line with this consideration, MRZ-99030 was able to prevent Aβ-induced toxicity on PC12 cells, retinal ganglion cells and retinal pigment epithelium cells when present at a 10-20 fold stoichiometric excess over Aβ. Moreover, in vivo studies demonstrate the neuroprotective potential of MRZ-99030 after systemic and topical administration in animal models of Alzheimer's disease and glaucoma/AMD respectively.

Keywords: Age related macular degeneration (AMD); Aggregation modulator; Alzheimer's disease; Atomic force microscopy (AFM); Dynamic light scattering (DLS); Fluorescence resonance energy transfer (TR-FRET); Glaucoma; Oligomers; SDS-PAGE; β-amyloid.

MeSH terms

  • Amyloid beta-Peptides / drug effects*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure
  • Animals
  • Cell Line, Tumor
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology*
  • Humans
  • Melanins / metabolism
  • Mice
  • Microscopy, Atomic Force
  • Neuroblastoma / pathology
  • Peptide Fragments / drug effects*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Peptide Fragments / ultrastructure
  • Silver Staining
  • Spectrum Analysis
  • Surface Plasmon Resonance
  • Time Factors
  • Tritium / pharmacokinetics

Substances

  • 2-(2-amino-3-(1H-indol-3-yl)propionylamino)-2-methylpropionic acid
  • Amyloid beta-Peptides
  • Dipeptides
  • Melanins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Tritium