Characterization of cholyl-leu-val-phe-phe-ala-OH as an inhibitor of amyloid beta-peptide polymerization

Abstract

Cholyl-LVFFA-OH (1, PPI-368) is an organic-modified peptide based on the sequence of amyloid beta-peptide (A beta). It is a potent and selective inhibitor of A beta polymerization that blocks the formation of neurotoxic species of A beta. In a nucleation-dependent polymerization assay of 50 microM A beta(1-40), equimolar concentrations of PPI-368 block polymerization based on turbidity and electron microscopy. Monomeric A beta(1-40) and A beta(1-42) are non-toxic when incubated with neuronal cell lines, but become toxic during polymerization. PPI-368 coordinately delays the onset of polymerization and the formation of neurotoxic A beta species for both peptides. In a polymerization extension assay seeded with pre-formed A beta polymer, similar inhibition and dose-dependency phenomena are observed with PPI-368. Radiolabeled PPI-368 is incorporated into fibrils during polymerization demonstrating binding to A beta peptide within afibrillar structure. Gel-filtration studies show progressive disappearance of A beta monomer and concomitant appearance of soluble higher molecular weight oligomers. In the presence of submolar concentrations of PPI-368, monomeric A beta is still present and oligomers are not observed PPI-368 does not inhibit the polymerization of other amyloidogenic proteins such as transthyretin (TTR) or islet amyloid polypeptide (IAPP(20-29).

Disrupting β-Amyloid Aggregation for Alzheimer Disease Treatment

“…Following these promising results, this group's strategy was to add to the recognition element a bulky group in order to interfere with Aβ polymerization [82,83]. They generated several derivatives of Aβ with Nterminal modifications.…”

“…Equimolar concentrations of cholyl-LVFFA-OH potently inhibit the nucleation of Aβ as well as the polymerization in pre-seeded fibril extension assays. In addition, it was shown that cholyl-LVFFA-OH delays the onset of polymerization and the formation of neurotoxic amyloid species for both peptides Aβ(1-40) and A β(1-42), protecting neuronal cell lines against Aβ toxicity [83]. Unfortunately, the use of cholyl-LVFFA-OH as a therapeutic agent is restricted by its large propensity to be cleared up almost completely after the hepatic first pass [83].…”

The Role of Aβ Peptides in Alzheimers Disease

“…The five residue sequence, LPFFD, has attracted attention as a β-sheet breaking peptide. The sequence closely resembles the Aβ peptide residues L 17 VFFA 21 , and has been shown to prevent polymerisation of Aβ in vitro [113]. It has also been proposed that AD may be treated by intervention/prevention of fibrillogenesis, and characterisation of the kinetic parameters of fibril formation with the intention of identifying a vulnerable structural transition has commenced [70].…”

Anti‐Misfolding and Anti‐Fibrillization Therapies for Protein Misfolding Disorders

“…The anionic disrupting compound KLVFFEEEE had similar effects, whereas the neutral compound KLVFFSSSS was ineffective, suggesting that the charged nature of the disrupting element is critical [55]. A different approach to design aggregation inhibitors was to add a bulky group to the recognition sequence, creating an inhibitor through steric hindrance [56,57]. The incorporation of N-methyl amino acids into peptides as disrupting elements has also been used by several investigators [58,59].…”