Peptide and Protein Mimetics Inhibiting Amyloid β-Peptide Aggregation

Abstract

Protein misfolding is related to some fatal diseases including Alzheimer's disease (AD). Amyloid beta-peptide (Abeta) generated from amyloid precursor protein can aggregate into amyloid fibrils, which are known to be a major component of Abeta deposits (senile plaques). The fibril formation of Abeta is typical of a nucleation-dependent process through self-recognition. Moreover, during fibrillization, several metastable intermediates such as soluble oligomers, including Abeta-derived diffusible ligands (ADDLs) and Abeta*56, are produced, which are thought to be the most toxic species to neuronal cells. Therefore, construction of molecules that decrease the Abeta aggregates, including soluble oligomers, protofibrils, and amyloid fibrils, might further our understanding of the mechanism(s) behind fibril formation and enable targeted drug discovery against AD. To this aim, various peptides and peptide derivatives have been constructed using the "Abeta binding element" based on the structural models of Abeta amyloid fibrils and the mechanisms of self-assembly. The central hydrophobic amino acid sequence, LVFF, of Abeta is a key sequence to self-assemble into amyloid fibrils. By combination of this core sequence with a hydrophobic or hydrophilic moiety, such as cholic acid or aminoethoxy ethoxy acetic acid units, respectively, good inhibitors of Abeta aggregation can be designed and synthesized. A peptide, LF, consisting of the sequence Ac-KQKLLLFLEE-NH 2, was designed based on the core sequence of Abeta but with a simplified amino acid sequence. The LF peptide can form amyloid-like fibrils that efficiently coassemble with mature Abeta1-42 fibrils. The LF peptide was also observed to immediately transform the soluble oligomers of Abeta1-42, which are thought to pose toxicity in AD, into amyloid-like fibrils. On the other hand, two Abeta-like beta-strands with a parallel orientation were embedded in green fluorescent protein (GFP), comprised of a beta-barrel structure, to make pseudo-Abeta beta-sheets on its surface. The GFP variant P13H binds to Abeta1-42 and inhibits Abeta1-42 oligomerization effectively in a substoichiometric condition. Thus, molecules capable of binding to Abeta can be designed based on structural similarities with the Abeta molecule. The peptide and protein mimetics based on the structural features of Abeta might lead to the development of drug candidates against AD.

Morphology‐Specific Inhibition of β‐Amyloid Aggregates by 17β‐Hydroxysteroid Dehydrogenase Type 10

“…[22] In transgenic mouse models for AD and in human AD sufferers, 17-HSD10 has been shown to have increased expression levels and has gained considerable attention as a result of its ability to bind A, suppress A-induced apoptosis and free-radical generation in neurons. [11] It is known that the interaction between 17-HSD10 and A , A and A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) takes place in the nanomolar range (K d ~ 40-80 nM), [11] which agrees well with the low cellular concentrations of A peptide expected at the early stages of AD. In addition, mutagenesis and inhibition studies have suggested that the L D loop of 17-HSD10, comprising residues C91-D119, plays a critical role in A binding.…”

“…However, a lack of -sheet structure at acidic pH cannot exclusively account for the observed lack of aggregation inhibition, as it has been shown that 17-HSD10 does not bind A (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), which is known to exhibit a -sheet conformation by CD and NMR studies. [63] In contrast, the conformation of the N-terminal region, residues 17-20 of A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) that constitute the binding interface with 17-HSD10, [11] is known to exhibit a random-coil/-helix/-sheet equilibrium that is highly dependent on pH conditions. [61,63,64] At pH 7-8, it has been demonstrated that residues 10-28, containing the putative 17-HSD10 binding interface, are in equilibrium between random coil and -helix conformations.…”

“…Nevertheless, it has been shown that the polymerization of the -amyloid peptide (A) into amyloid fibrils, and other morphologies including plaques and oligomeric species, constitutes a hallmark of AD. [4] The development of A inhibitors has thus received much attention, with peptides [5][6][7] and small organic molecules [8][9][10] now established as the two main classes of amyloid inhibitors. A production, aggregation and accumulation within the brain is summarised in Figure 1.…”

“…[17][18][19][20][21][22] For instance, the 17-hydroxysteroid dehydrogenase type 10 (17-HSD10) or also commonly known as amyloid-binding alcohol dehydrogenase (ABAD)) [21,[23][24][25][26] constitutes one of such mitochondrial A-interacting proteins. [6,27] 17-HSD10 is a 27 kDa multifunctional enzyme expressed in all cell types and is thought to play a central role in the -oxidation of fatty acids, [24,28] isoleucine degradation, catalysis and oxidation of alcohols and the reduction of aldehydes and ketones. [22] In transgenic mouse models for AD and in human AD sufferers, 17-HSD10 has been shown to have increased expression levels and has gained considerable attention as a result of its ability to bind A, suppress A-induced apoptosis and free-radical generation in neurons.…”

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

“…Our work is inspired by previous studies that demonstrated the ability of amyloidogenic peptide fragments to inhibit fibrillization of polypeptides containing the cognate peptide sequences (25)(26)(27)(28)(29)(30)(31). A common concern when using amyloidogenic peptides as aggregation inhibitors is their poor solubility.…”