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

ABSTRACT

Therapeutic approaches addressing ß-amyloid1-42 (Aß1-42) 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 Aß aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric Aß species. The present study confirmed that MRZ-99030 prevents the formation of oligomeric Aß 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 Aß, but rather promotes the formation of large, non-amyloidogenic, amorphous Aß aggregates and thereby reduces the amount of intermediate toxic soluble oligomeric Aß species. The affinity of MRZ-99030 to Aß1-42 determined by SPR was 28.4 nM but the ratio of compound to Aß is also important a 10-20 fold excess of MRZ-99030 over Aß is probably required for effective modulation of protein/protein interactions. For example, in glaucoma, assuming a maximal Aß 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 Aß-induced toxicity on PC12 cells, retinal ganglion cells and retinal pigment epithelium cells when present at a 10-20 fold stoichiometric excess over Aß. 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.