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

Therapeutic approaches addressing ?-amyloid1-42 (A?1-42) 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 A? aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric A? species. The present study confirmed that MRZ-99030 prevents the formation of oligomeric A? 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 A?, but rather promotes the formation of large, non-amyloidogenic, amorphous A? aggregates and thereby reduces the amount of intermediate toxic soluble oligomeric A? species. The affinity of MRZ-99030 to A?1-42 determined by SPR was 28.4 nM but the ratio of compound to A? is also important: a 10-20 fold excess of MRZ-99030 over A? is probably required for effective modulation of protein/protein interactions. For example, in glaucoma, assuming a maximal A? 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 A?-induced toxicity on PC12 cells, retinal ganglion cells and retinal pigment epithelium cells when present at a 10-20 fold stoichiometric excess over A?. 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.     «

Therapeutic approaches addressing ?-amyloid1-42 (A?1-42) 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 A? aggregation modulator, previously reported to prevent the formation of soluble toxic oligomeric A? species. The...     »