A Metalloporphyrin-Peptide Conjugate as an Effective Inhibitor of Amyloid-β Peptide Fibrillation and Cytotoxicity

Abstract

Molecules that inhibit Aβ misfolding have received considerable attention in view of their potential use in the prevention or treatment of Alzheimer's disease. We designed a peptide‐porphyrin conjugate incorporating two recognition sites enabling it to interact strongly with the Aβ42 peptide. The inhibitory effect on Aβ42 fibril formation was determined in aqueous solution by a variety of spectroscopic techniques including UV‐vis, fluorescence, Circular Dichroism, Dynamic Light Scattering, Maldi‐Time of Flight‐Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy. A working mechanism of the antifibrillogenic action of the conjugate was proposed based on the experimental observations. The neuroprotective activity of the conjugate was also inferred by using primary neuronal or neuron‐like differentiated SH‐SY5Y cell cultures.

Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity

“…We found that THPP and bCD weren ot able to prevent oligomert oxicity. The His residues may coordinate zinc(II) of ZnCDTHPP,f urtherc ontributingt oh amper the peptideh ydrolysis close by.T he interaction between az inc-coordinated porphyrin conjugate and the histidine residues of the Ab 42 N-terminus has been previously evoked, [11] thus supporting the mechanism we hypothesized.Overall, the proteomic analysiso ft he Ab 42 fragments reveals that CDTHPP and ZnCDTHPP interact with aw ide sequence region of Ab 42 ,e ncompassing an LVFF motif, which is involved in the self-recognition mechanism of the amyloid aggregation and is common to most AD b-sheetb reaker peptides. These datac onfirm that CDTHPP and ZnCDTHPP show an europrotective activity arising from the synergyo ft he THPP and bCD properties and possess unique anti-oligomeric activity not found in the parentc ompounds.S uch resultss uggest that CDTHPP conjugatesi nterfere with Ab 42 ,blockingi ts cytotoxicity.…”

“…In this work, the biological properties of 5[4-(6-O-b-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrina nd its zinc complex were tested, as new molecules that interactw ith Ab and effectively preventi ts cytotoxicity.W ef ound that these systems can cross the cell membrane to deliver Ab intracellularlya nd promote its clearance. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. Much efforth as therefore been made to investigate the compositiono fa myloid plaques, the mechanism underlying Ab fibril formation,a nd the parameters that could contribute to the Ab toxicity.…”

“…[4] Several small molecules, including tetrapyrrolic compounds, have been reported to modulate the amyloid aggregation of several proteins, such as tau, Ab,a nd a-synuclein. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD.…”

“…[5,6] Among these,p hthalocyanines are the most commonly investigated compounds, [7][8][9] whereas the effect of porphyrins on Ab aggregationa nd toxicity has been less explored. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.…”

Porphyrin–peptide conjugates in biomedical applications

“…In vitro, the toxic effect of amyloid β peptides on neuron‐like cells (PC12) was greatly inhibited by the conjugate in a dose dependent manner, without effect on the cell viability. A possible mechanism of inhibition of amyloid β peptides formation by a zinc–porphyrin–KLVFF conjugate has been recently proposed, consisting in the generation of off‐pathway aggregated forms of amyloid β peptides not evolving into oligomeric or proto‐fibrillary toxic forms …”