title: 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).
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.
authors: Merz Pharmaceuticals, Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany. Electronic address: christopher.parsons@merz.de.
authors: Christopher G
authors: CG
authors: Parsons
authors: Merz Pharmaceuticals, Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany.
authors: Maarten
authors: M
authors: Ruitenberg
authors: Merz Pharmaceuticals, Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany.
authors: Christine E
authors: CE
authors: Freitag
authors: Merz Pharmaceuticals, Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany.
authors: Kamila
authors: K
authors: Sroka-Saidi
authors: Merz Pharmaceuticals, Eckenheimer Landstrasse 100, D-60318 Frankfurt, Germany.
authors: Hermann
authors: H
authors: Russ
authors: Department of Anaesthesiology, Technische Universität München, D-81675, Germany.
authors: Gerhard
authors: G
authors: Rammes
mesh_terms: D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008543:Melanins / Q000378:metabolism; D051379:Mice; D018625:Microscopy, Atomic Force; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000187:drug effects* / Q000378:metabolism* / Q000494:pharmacology / Q000648:ultrastructure; D016622:Silver Staining; D013057:Spectrum Analysis; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C000598750:2-(2-amino-3-(1H-indol-3-yl)propionylamino)-2-methylpropionic acid; D016229:Amyloid beta-Peptides; D004151:Dipeptides; D008543:Melanins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014316:Tritium
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