Antiamyloidogenic Activity of Aβ42-Binding Peptoid in Modulating Amyloid Oligomerization

Abstract

The oligomerization and aggregation of amyloid β (Aβ) play central role in the pathogenesis of Alzheimer's disease (AD). Molecular binding agents for modulating the formation of Aβ oligomers and fibrils have promising application potential in AD therapies. By screening a peptoid library using surface plasmon resonance imaging, amyloid inhibitory peptoid 1 (AIP1) that has high affinity to Aβ42 is identified. AIP1 is demonstrated to inhibit Aβ42 oligomerization and fibrillation and to rescue Aβ42-induced cytotoxicity through decreasing the content of Aβ42 oligomers that is related to cell membrane permeability. Molecular docking suggests that the binding sites of AIP1 may be at the N-terminus of Aβ42. The blood-brain barrier (BBB) permeability of AIP1 using an in vitro BBB model is also revealed. This work provides a strategy for the design and development of peptoid-based antiamyloidogenic agents. The obtained amyloid inhibitory peptoid shows prospects in the therapeutic application in AD.

A Systematic Review of Antiamyloidogenic and Metal-Chelating Peptoids: Two Structural Motifs for the Treatment of Alzheimer’s Disease

“…Yang et al recently discovered the nanomolar Aβ 1–42 inhibitor amyloid inhibitory peptoid 1 (AIP1; Figure 2 ). AIP1 increased the lag time to form the critical nucleus for fibril formation and demonstrated in vitro BBB permeability in line with that of previously reported Aβ-aggregation inhibitors ( Table 1 ) [ 40 ]. In addition to providing a viable lead for AD, this work presents an approach for the discovery of additional peptoid-based Aβ 1–42 aggregation inhibitors.…”

“…The amyloid-targeting peptoids presented in Section 2 contain aromatic, hydrophobic, and aliphatic residues to facilitate interactions with Aβ 1–40/42 and/or to improve BBB penetrability [ 40 , 42 ]. In addition, some of these peptoids contain hydrophilic residues (e.g., N lys, a lysine-based peptoid residue) to promote water solubility and chiral residues, in particular chiral aromatic residues (e.g., N -( S )-1-phenylethylglycine ( N spe)), to promote helicity [ 44 , 47 ].…”

Peptide‐Modified Mo Polyoxometalate Nanoparticles Suppress Zn2+‐Induced Aβ Aggregation

“…Mo-POMs: (H 2 O) 3 (NH 4 ) 18 [Mo 57 V 6 (NO3) 6 O 183 (H 2 O) 183 ] · 56 H 2 O (1) were prepared according to the literature. Peptide @ Mo-POMs was synthesized on the basis of further 1, the specific synthesis method was as follows: 1 mL of 200 μM Mo-POMs and 100 μL Peptide Ac-QKLVFF-NH2 peptide solution was mixed, stirred at room temperature for 30 min, Then aged at 4°C overnight.…”

“…[3] Numerous research efforts suggest that the brains of AD patients generally exhibit the following pathological features: reduced brain volume, decreased neurons and synapses in the hippocampus the accumulation of insoluble forms of amyloidβ (Aβ) in plaques, and aggregation of the microtubule protein tau in neurofibrillary tangles in neurons. [4][5][6] Several approved drugs ameliorate some of the symptoms of Alzheimer's disease, yet no disease-modifying treatment or a cure can achieve the radical cure of AD.…”

Peptoids: Emerging Therapeutics for Neurodegeneration

“…A distinct anti-amyloidogenic peptoid also exhibiting high affinity for Aβ 1-42 was identified via surface plasmon resonance from a library of more than 4,000 six-mer peptoids containing four variable residues. This peptoid inhibits both early stage oligomerization as well as the formation of mature aggregates and protects against Aβ-induced toxicity 25 . Through rational design, an eight-mer peptoid was developed to both mimic the five-residue hydrophobic core of Aβ and incorporate additional aromatic residues.…”