Phthalocyanines as Molecular Scaffolds to Block Disease-Associated Protein Aggregation

Abstract

The aggregation of proteins into toxic conformations plays a critical role in the development of different neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Creutzfled-Jakob's disease (CJD). These disorders share a common pathological mechanism that involves the formation of aggregated protein species including toxic oligomers and amyloid fibrils. The aggregation of alpha-synuclein (αS) in PD and the amyloid beta peptide (Aβ) and tau protein in AD results in neuronal death and disease onset. In the case of CJD, the misfolding of the physiological prion protein (PrP) induces a chain reaction that results in accumulation of particles that elicit brain damage. Currently, there is no preventive therapy for these diseases and the available therapeutic approaches are based on the treatment of the symptoms rather than the underlying causes of the disease. Accordingly, the aggregation pathway of these proteins represents a useful target for therapeutic intervention. Therefore, understanding the mechanism of amyloid formation and its inhibition is of high clinical importance. The design of small molecules that efficiently inhibit the aggregation process and/or neutralize its associated toxicity constitutes a promising tool for the development of therapeutic strategies against these disorders. In this accounts, we discuss current knowledge on the anti-amyloid activity of phthalocyanines and their potential use as drug candidates in neurodegeneration. These tetrapyrrolic compounds modulate the amyloid assembly of αS, tau, Aβ, and the PrP in vitro, and protect cells from the toxic effects of amyloid aggregates. In addition, in scrapie-infected mice, these compounds showed important prophylactic antiscrapie properties. The structural basis for the inhibitory effect of phthalocyanines on amyloid filament assembly relies on specific π-π interactions between the aromatic ring system of these molecules and aromatic residues in the amyloidogenic proteins. Analysis of the structure-activity relationship in phthalocyanines revealed that their anti-amyloid activity is highly dependent on the type of metal ion coordinated to the tetrapyrrolic system but is not sensitive to the number of peripheral charged substituents. The tendency of phthalocyanines to oligomerize (self-association) via aromatic-aromatic stacking interactions correlates precisely with their binding capabilities to target proteins and, more importantly, determines their efficiency as anti-amyloid agents. The ability to block different types of disease-associated protein aggregation raises the possibility that these cyclic tetrapyrrole compounds have a common mechanism of action to impair the formation of a variety of pathological aggregates. Because the structural and molecular basis for the anti-amyloid effects of these molecules is starting to emerge, combined efforts from the fields of structural, cellular, and animal biology will result critical for the rational design and discovery of new drugs for the treatment of amyloid...

Activity of Zn and Mg phthalocyanines and porphyrazines in amyloid aggregation of insulin

“…Generally, the structural basis for the effect of macrocyclic compound on amyloid fibril formation relies on specific π‐π interactions between the aromatic ring system of these molecules and aromatic residues of protein 4. However, we suppose that due to the mentioned “affinity” of Zn to histidine residue, Zn and Mg complexes could prefer different sites into the insulin amyloidogenic region for their binding.…”

“…Polyaromatic scaffolds belonging to chemical classes of porphyrins and phthalocyanines are widely studied as high potential anti‐amyloidogenic agents 4, 5, 6. Among such compounds, metal‐containing tetrasulfonated phthalocyanines (Figure S1 in Supporting Information) have been described as efficient inhibitors of α‐synuclein fibrillization 5.…”

“…Polyaromatic scaffolds belonging to chemical classes of porphyrins and phthalocyanines are widely studied as high potential antiamyloidogenic agents. [4][5][6] Among such compounds, metal-containing tetrasulfonated phthalocyanines ( Figure S1 in Supporting Information) have been described as efficient inhibitors of α-synuclein fibrillization. 5 According to this study, the inhibitory activity noticeably depends on Previously, we have discovered the anti-fibrillogenic activity of axially coordinated phthalocyanines ( Figure S3 in Supporting Information) that are the complexes with "spatial geometry" of the molecule.…”

Characterizing the inhibition of α‐synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP

“…The second notable feature of the C-terminal domain is that it contains three of the four tyrosine residues of the protein (Y125, Y133, and Y136), which could interact specifically and strongly with Fe-TMPyP via π-π interactions between the aromatic rings of the tetrapyrrole and tyrosine residues to modulate aggregation. 74 Indeed, the peaks for Y125 and Y136 were absent with Fe-TMPyP bound, although Y133 could not be assigned with confidence. Furthermore, previous work found that α-synuclein aggregation could be attenuated by a small molecule (fasudil) that interacted specifically with Y133 and Y136, 75 suggesting that interactions with the C-terminal tyrosines might provide a route to suppress aggregation.…”

“…The second notable feature of the C‐terminal domain is that it contains three of the four tyrosine residues of the protein (Y125, Y133, and Y136), which could interact specifically and strongly with Fe‐TMPyP via π–π interactions between the aromatic rings of the tetrapyrrole and tyrosine residues to modulate aggregation . Indeed, the peaks for Y125 and Y136 were absent with Fe‐TMPyP bound, although Y133 could not be assigned with confidence.…”