Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies

Abstract

Neurodegeneration in Alzheimer’s disease (AD) is defined by pathology featuring amyloid-β (Aβ) deposition in the brain. Aβ monomers themselves are generally considered to be nontoxic, but misfold into β-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to Aβ and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against Aβ(1–42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind Aβ in anti-parallel orientation, demonstrated neuroprotection against Aβ(1–42). A third inhibitor, predicted to bind parallel to Aβ, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against Aβ toxicity.

Chiral Linked Systems as a Model for Understanding D-Amino Acids Influence on the Structure and Properties of Amyloid Peptides

“…The choice of NSAIDs is not accidental, since the derivatives of these drugs are now being tested as inhibitor of γ-secretase-a complex of enzymes involved in the synthesis of Aβ42 from precursor of amyloid protein (APP) [18,19]. The mechanisms of the Aβ42 monomer action and its aggregated forms have been studied in cell models, while the primary cause of the formation of aggregates and their relationship with the inclusion of D-amino acids in biomolecules remains to be studied [3,4,[9][10][11]. This review describes first results on the influence of D-amino acids on the structure and properties, obtained in the study of model systems (Figure 1).…”

“…The mechanisms of the Aβ42 monomer action and its aggregated forms have been studied in cell models, while the primary cause of the formation of aggregates and their relationship with the inclusion of D-amino acids in biomolecules remains to be studied [ 3 , 4 , 9 , 10 , 11 ]. This review describes first results on the influence of D-amino acids on the structure and properties, obtained in the study of model systems ( Figure 1 ).…”

“…The main goal of this review is to show that model systems can shed light on some significant problems for understanding the nature of the neurodegenerative diseases: the actual mechanism of chiral inversion (transformation of L-amino acids to D-analogs) and differences in the behavior of systems with L- and D-optical isomers of amino acids [ 1 ]. Furthermore, many sources point to the toxic effects of free radicals and reactive oxygen species on the progression of neurodegenerative ailments [ 5 , 6 , 7 , 8 , 9 ]. The review presents a section describing the factors affecting chiral inversion in biological and model systems, as well as the evidence for the participation of radical species and metals with variable valence in this process.…”

Brain Delivery of Curcumin Through Low-Intensity Ultrasound-Induced Blood–Brain Barrier Opening via Lipid-PLGA Nanobubbles

“…[7][8][9] However, many potential PD pharmacological agents have no or limited therapeutic efficacies due to their low druggability and poor permeation across blood-brain barrier (BBB). [10][11][12] Therefore, there is an urgent demand to find novel strategies for improving their druggability and favoring their brain delivery in vivo with minimal adverse effects in the central nervous.…”

Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research

“…As described in Robinson et al’s report [ 14 ], peptide-based Aβ aggregation inhibitors are potential preventative strategies that have some advantages as compared to monoclonal antibodies (mAbs), including low immunological profile, small size, and tunable, drug-like characteristics.…”