Rationally designed peptoids modulate aggregation of amyloid-beta 40.
Ontology highlight
ABSTRACT:
SUBMITTER: Turner JP
PROVIDER: S-EPMC4102963 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Advances in the understanding of Alzheimer's disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro, PMN310 inhibited AßO propagation and toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.
| S-EPMC6614461 | biostudies-literature
Project description:Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-? protein (1-42) and amyloid-? protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of A?42 is more downhill, with a computed solubility that is about 10 times smaller than that of A?40. At a concentration of 40 ?M, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the A?40 aggregation landscape disappears for A?42, suggesting that the A?42 tetramer has a more diverse structural range. To further compare the landscapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on ?-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that A?40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for A?42 relative to A?40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.
| S-EPMC5805378 | biostudies-literature
Project description:Some polyphenols, which are common natural compounds in fruits, vegetables, seeds, and oils, have been considered as potent inhibitors of amyloid beta (A?) aggregation, one critical pathogenic event in Alzheimer's disease (AD). However, the mechanisms by which polyphenols affect aggregation are not fully understood. In this study, we aimed to investigate the effect of two classes of polyphenols (flavonoids and stilbenes) on the self-assembly of A?_42, in particular, how this relates to structure. We found that the flavonoids gallocatechin gallate (GCG) and theaflavin (TF) could completely inhibit A? aggregation, while two stilbenes, resveratrol and its glucoside derivative piceid, could also suppress A? aggregation, but to a much lesser extent. Intriguingly, resveratrol accelerated the formation of A? fibrils before its decreasing effect on fibrillation was detected. Atomic force microscopy (AFM) images showed a huge mass of long and thin A? fibrils formed in the presence of resveratrol. Although the morphology was the same in the presence of piceid, the fibrils were sparse in the presence of picead. In the presence of flavonoids, A? morphology was unchanged from prior to incubation (0 h), in agreement with amyloid beta kinetics analysis using thioflavin-T fluorescence assay. The electrochemical data showed a higher ability of GCG and TF to interact with A? than resveratrol and piceid, which could be attributed to the presence of more aromatic rings and hydroxyl groups. In addition, the two flavonoids exhibited a similar propensity for A? aggregation, despite having some differences in their structure. However, in the case of stilbenes, the addition of a glucoside at C-7 slightly decreased anti-A? aggregation property compared to resveratrol. These findings contribute to a better understanding of the essential structural features of polyphenols required for inhibiting A? aggregation, and the possible mechanisms for modulating aggregation.
| S-EPMC6521010 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common form of dementia and currently affects 5.4 million Americans. A number of anti-A? (beta amyloid) therapeutic agents have been developed for AD, but so far all of them failed in clinic. Here we used peptoid chemistry to develop ligands selective for A?42. Peptoids are N-substituted glycine oligomers, a class of peptidomimics. We synthesized an on-bead peptoid library consisting of 38,416 unique peptoids. The generated peptoid library was screened and arrays of A?42-selective peptoid ligands were identified. One of those peptoid ligands, IAM1 (inhibitor of amyloid), and the dimeric form (IAM1)2 were synthesized and evaluated in a variety of biochemical assays. We discovered that IAM1 selectively binds to A?42, while the dimeric derivative (IAM1)2 has a higher affinity for A?42. Furthermore, we demonstrated that IAM1 and (IAM1)2 were able to inhibit the aggregation of A?42 in a concentration-dependent manner, and that (IAM1)2 protected primary hippocampal neurons from the A?-induced toxicity in vitro. These results suggest that IAM1 and (IAM1)2 are specific A?42 ligands with antiaggregation and neuroprotective properties. IAM1, (IAM1)2, and their derivatives hold promise as A?42 detection agents and as lead compounds for the development of AD therapeutic agents.
| S-EPMC3689191 | biostudies-literature
Project description:The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14-23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways.
| S-EPMC4466325 | biostudies-literature
Project description:The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A?) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A?(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 ?M spermine (normal intracellular concentration is ~1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A?(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A? peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
| S-EPMC3605822 | biostudies-literature
Project description:Aggregation states of amyloid beta peptides for amyloid beta A β 1 - 40 to A β 1 - 42 and A β p 3 - 42 are investigated through small angle neutron scattering (SANS). The knowledge of these small peptides and their aggregation state are of key importance for the comprehension of neurodegenerative diseases (e.g., Alzheimer's disease). The SANS technique allows to study the size and fractal nature of the monomers, oligomers and fibrils of the three different peptides. Results show that all the investigated peptides have monomers with a radius of gyration of the order of 10 Å, while the oligomers and fibrils display differences in size and aggregation ability, with A β p 3 - 42 showing larger oligomers. These properties are strictly related to the toxicity of the corresponding amyloid peptide and indeed to the development of the associated disease.
| S-EPMC6747079 | biostudies-literature
Project description:To visualize amyloid β (Aβ) aggregates requires an uncontaminated and artifact-free interface. This paper demonstrates the interface between graphene and pure water (verified to be atomically clean using tunneling microscopy) as an ideal platform for resolving size, shape, and morphology (measured by atomic force microscopy) of Aβ-40 and Aβ-42 peptide assemblies from 0.5 to 150 hours at a 5-hour time interval with single-particle resolution. After confirming faster aggregation of Aβ-42 in comparison to Aβ-40, a stable set of oligomers with a diameter distribution of ~7 to 9 nm was prevalently observed uniquely for Aβ-42 even after fibril appearance. The interaction energies between a distinct class of amyloid aggregates (dodecamers) and graphene was then quantified using molecular dynamics simulations. Last, differences in Aβ-40 and Aβ-42 networks were resolved, wherein only Aβ-42 fibrils were aligned through lateral interactions over micrometer-scale lengths, a property that could be exploited in the design of biofunctional materials.
| S-EPMC7141833 | biostudies-literature
Project description:Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-amyloid related β-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ1-42. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aβ1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic β-hairpin targeting other types of amyloid-forming proteins.
| S-EPMC5359901 | biostudies-literature
Project description:Human islet amyloid polypeptide (hIAPP or amylin) is a polypeptide hormone produced in the pancreatic ?-cells that plays a role in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes and is a promising adjunct to insulin therapy. However, hIAPP rapidly forms amyloid, and its strong tendency to aggregate limits its usefulness. The process of hIAPP amyloid formation is toxic to cultured ?-cells and islets, and islet amyloid formation in vivo has been linked to ?-cell death and islet graft failure. An analogue of hIAPP with a weakened tendency to aggregate, denoted pramlintide (PM), has been approved for clinical applications, but suffers from poor solubility, particularly at physiological pH, and its unfavorable solubility profile prevents coformulation with insulin. We describe a strategy for rationally designing analogues of hIAPP with improved properties; key proline mutations are combined with substitutions that increase the net charge of the molecule. An H18R/G24P/I26P triple mutant and an H18R/A25P/S28P/S29P quadruple mutant are significantly more soluble at neutral pH than hIAPP or PM. They are nonamyloidogenic and are not toxic to rat INS ?-cells. The approach is not limited to these examples; additional analogues can be designed using this strategy. To illustrate this point, we show that an S20R/G24P/I26P triple mutant and an H18R/I26P double mutant are nonamyloidogenic and significantly more soluble than human IAPP or PM. These analogues and second-generation derivatives are potential candidates for the coformulation of IAPP with insulin and other polypeptides.
| S-EPMC4172205 | biostudies-literature