Cyclic Peptides as Inhibitors of Amyloid Fibrillation

Luo, Jinghui; Abrahams, Jan Pieter

doi:10.1002/chem.201304253

Cited by 45 publications

(94 citation statements)

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“…These inhibitors showed good activity in both inhibition and dissolution of Ab42 aggregates. 93 CP are metabolized slowly than their non-cyclic analogues and hence display higher bioavailability. To understand the role of 5 and 6 in dissolving Ab42 and activating autophagy, an autophagy-defective mutant (Datg1 mutant) was used to perform growth analysis which showed no rescue in yeast cells.…”

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confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

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Section: View Article Onlinementioning

confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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“…Although molecules such as ␤-sheet breakers (97) and cyclic peptides (98,99) have been devised to prevent amyloid aggregation, traditional antibodies have so far provided the best preliminary treatment results, at least for AD (100). It is unclear to what extent current amyloid inhibitors will block the formation of amyloid co-aggregates.…”

Section: Implications Of A␤ Cross-amyloid Interactionsmentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

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124

103

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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“…Fueled by a growing body of structural information on amyloids, including their toxic oligomers, as well as evidence that the formation of amyloids entails equilibrium processes, the last few decades have seen major efforts directed toward designing and developing inhibitors that target such equilibria. Heterocyclic peptides are attractive for this purpose, because they can be effectively synthesized and diversified by chemical methods (reviewed in [162]). …”

Section: Discussionmentioning

confidence: 99%

Anti-amyloidogenic Heterocyclic Peptides

Chemerovski-Glikman

Richman

Rahimipour

2016

Topics in Heterocyclic Chemistry

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The amyloid fibril is a highly ordered proteinous aggregate, originally discovered in the context of the self-assembly of soluble proteins into insoluble extracellular plaques. The molecular structure of amyloidosis, an energetically stable conformation with a thermodynamic local minimum, is of particular interest because of its possible pathogenicity. Amyloidogenic diseases (amyloidoses) are often fatal, widely heterogenic, and caused by sporadic, genetic, or infectious pathogens. Consequently, major effort has been directed in the past few decades to identify and develop agents that decrease the concentration of the pathogenic aggregates either by interfering with the self-assembly of the proteins or by modulating their physiological concentration. Heterocyclic peptides of natural and synthetic origin have gained special attention because of their demonstrated ability to interact with various amyloids. In addition to interfering with the amyloid aggregation process, many of the discovered peptides also inhibit the formation of fibrils, disassemble preformed fibrils, and prevent the pathogenic seeding effect. Others are instrumental candidates for passive vaccination against amyloid deposits. The promising preliminary results described here, together with the broad chemical diversity of heterocyclic peptides and their amenability to largescale production, make these compounds promising for anti-amyloidogenic research and for pharmacological therapy of amyloidoses.

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Cyclic Peptides as Inhibitors of Amyloid Fibrillation

Cited by 45 publications

References 65 publications

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Anti-amyloidogenic Heterocyclic Peptides

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