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Amyloid Inhibitors and Modulators
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Amyloid Inhibitors and Modulators

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 37665

Special Issue Editor

Dr. Gal Bitan

E-Mail Website
Guest Editor
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Interests: neurodegenerative proteinopathies; atypical parkinsonian disorders

Special Issue Information

Dear Colleagues,

The abnormal self-assembly of proteins into toxic oligomers and aggregates underlies over 30 diseases called proteinopathies. Though many of these diseases affect the central nervous system, infamous examples are Alzheimer’s and Parkinson’s diseases, others attack a particular organ, such as the pancreas in type-2 diabetes, or are systemic, e.g., light-chain amyloidosis and dialysis-related amyloidosis. As the common characteristic of all of these diseases is the abnormal self-assembly process, developing compounds and biologics that inhibit or otherwise perturb this process is an attractive therapeutic strategy for proteinopathies. Disease-modifying therapy for one rare disease—familial amyloidotic polyneuropathy caused by transthyretin—has become available recently, yet for the major diseases, most notoriously Alzheimer’s disease, the recent history has been of multiple failures, including of high-profile, late-phase clinical trials. This grim status, and the pressure caused by increasing incidence numbers of people affected by Alzheimer’s disease and other proteinopathies have raised several important questions. Are we aiming at the right targets? Are we using the right strategies to obtain effective drugs for proteinopathies? Can we use common strategies for multiple diseases or will we need to tailor specific drugs for specific diseases? Are there advantages to drug candidates hitting multiple targets (e.g., both aggregation and inflammation) or are we creating a difficult optimization challenge when compounds have more than one activity? Is targeting prion-like cell-to-cell spreading more or less important than inhibiting the direct toxicity of amyloidogenic proteins? What are the most important structures to target?

This Special Issue of Molecules focused on “Amyloid Inhibitors and Modulators” aims to address many or all of these questions, presenting a perspective on the current state of research in this field, and including research articles demonstrating a variety of strategies for tackling this difficult and pressing problem. 

Dr. Gal Bitan
Guest Editor

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Keywords

  • Amyloid
  • fibril
  • oligomer
  • Alzheimer’s disease
  • Parkinson’s disease
  • amyloidosis
  • proteinopathy
  • proteotoxicity
  • inhibitor
  • modulator
  • drug discovery
  • drug design
  • drug development

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Published Papers (7 papers)

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Research

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21 pages, 2847 KiB  
Article
Interference with Amyloid-β Nucleation by Transient Ligand Interaction
by Tao Zhang, Jennifer Loschwitz, Birgit Strodel, Luitgard Nagel-Steger and Dieter Willbold
Molecules 2019, 24(11), 2129; https://doi.org/10.3390/molecules24112129 - 5 Jun 2019
Cited by 10 | Viewed by 5485
Abstract
Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting [...] Read more.
Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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14 pages, 2657 KiB  
Communication
Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid
by Guru KrishnaKumar Viswanathan, Satabdee Mohapatra, Ashim Paul, Elad Arad, Raz Jelinek, Ehud Gazit and Daniel Segal
Molecules 2018, 23(12), 3279; https://doi.org/10.3390/molecules23123279 - 11 Dec 2018
Cited by 13 | Viewed by 3921
Abstract
PAP248–286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of [...] Read more.
PAP248–286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of amyloid formation by PAP248–286 (termed PAP f39) may likely reduce HIV transmission in AIDS. In this study, we show that the naphthoquinone tryptophan (NQTrp) hybrid molecule significantly inhibited PAP f39 aggregation in vitro in a dose-dependent manner as observed from the ThT assay, ANS assay, and transmission electron microscopy imaging. We found that even at a sub-molar concentration of 20:1 [PAP f39:NQTrp], NQTrp could reduce >50% amyloid formation. NQTrp inhibition of PAP f39 aggregation resulted in non-toxic intermediate species as determined by the vesicle leakage assay. Isothermal titration calorimetry and molecular docking revealed that the binding of NQTrp and PAP f39 is spontaneous, and NQTrp predominantly interacts with the polar and charged residues of the peptide by forming hydrogen bonds and hydrophobic contacts with a strong binding energy. Collectively, these findings indicate that NQTrp holds significant potential as a small molecule inhibitor of semen amyloids. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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Review

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23 pages, 2584 KiB  
Review
Yeast Models for Amyloids and Prions: Environmental Modulation and Drug Discovery
by Tatiana A. Chernova, Yury O. Chernoff and Keith D. Wilkinson
Molecules 2019, 24(18), 3388; https://doi.org/10.3390/molecules24183388 - 18 Sep 2019
Cited by 19 | Viewed by 4919
Abstract
Amyloids are self-perpetuating protein aggregates causing neurodegenerative diseases in mammals. Prions are transmissible protein isoforms (usually of amyloid nature). Prion features were recently reported for various proteins involved in amyloid and neural inclusion disorders. Heritable yeast prions share molecular properties (and in the [...] Read more.
Amyloids are self-perpetuating protein aggregates causing neurodegenerative diseases in mammals. Prions are transmissible protein isoforms (usually of amyloid nature). Prion features were recently reported for various proteins involved in amyloid and neural inclusion disorders. Heritable yeast prions share molecular properties (and in the case of polyglutamines, amino acid composition) with human disease-related amyloids. Fundamental protein quality control pathways, including chaperones, the ubiquitin proteasome system and autophagy are highly conserved between yeast and human cells. Crucial cellular proteins and conditions influencing amyloids and prions were uncovered in the yeast model. The treatments available for neurodegenerative amyloid-associated diseases are few and their efficiency is limited. Yeast models of amyloid-related neurodegenerative diseases have become powerful tools for high-throughput screening for chemical compounds and FDA-approved drugs that reduce aggregation and toxicity of amyloids. Although some environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. Environmental stresses trigger amyloid formation and loss, acting either via influencing intracellular concentrations of the amyloidogenic proteins or via heterologous inducers of prions. Studies of environmental and physiological regulation of yeast prions open new possibilities for pharmacological intervention and/or prophylactic procedures aiming on common cellular systems rather than the properties of specific amyloids. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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20 pages, 1108 KiB  
Review
Autophagy Modulation as a Treatment of Amyloid Diseases
by Zoe Mputhia, Eugene Hone, Timir Tripathi, Tim Sargeant, Ralph Martins and Prashant Bharadwaj
Molecules 2019, 24(18), 3372; https://doi.org/10.3390/molecules24183372 - 16 Sep 2019
Cited by 48 | Viewed by 6651
Abstract
Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein [...] Read more.
Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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20 pages, 6937 KiB  
Review
Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies
by Qiuchen Zheng, Micheal T. Kebede, Merc M. Kemeh, Saadman Islam, Bethany Lee, Stuart D. Bleck, Liliana A. Wurfl and Noel D. Lazo
Molecules 2019, 24(12), 2316; https://doi.org/10.3390/molecules24122316 - 22 Jun 2019
Cited by 56 | Viewed by 5676
Abstract
The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer’s disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show [...] Read more.
The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer’s disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymatic processing of the amyloid-β precursor protein and inhibit toxic Aβ oligomerization by enhancing the clearance of Aβ42 monomer, modulating monomer–monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau β-sheet formation. The anti-Aβ-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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10 pages, 894 KiB  
Review
Do We Need Anti-Prion Compounds to Treat Alzheimer’s Disease?
by Dieter Willbold and Janine Kutzsche
Molecules 2019, 24(12), 2237; https://doi.org/10.3390/molecules24122237 - 15 Jun 2019
Cited by 14 | Viewed by 5165
Abstract
Background: While phase III clinical trials for the treatment of Alzheimer’s disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of [...] Read more.
Background: While phase III clinical trials for the treatment of Alzheimer’s disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs. Objectives: We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment. Method: We collected publicly accessible pre-clinical efficacy data of Aβ targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prion compound and compare it the properties of past and current phase III drug candidates. Results: We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aβ-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aβ oligomers. Conclusion: RD2 is the first anti-prion drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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15 pages, 2716 KiB  
Review
Three Structural Features of Functional Food Components and Herbal Medicine with Amyloid β42 Anti-Aggregation Properties
by Kazuma Murakami and Kazuhiro Irie
Molecules 2019, 24(11), 2125; https://doi.org/10.3390/molecules24112125 - 5 Jun 2019
Cited by 26 | Viewed by 5190
Abstract
Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). There are numerous naturally occurring products that suppress the aggregation of Aβ42, but the underlying mechanisms remain to be elucidated. Based on NMR and MS spectroscopic analysis, we propose [...] Read more.
Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). There are numerous naturally occurring products that suppress the aggregation of Aβ42, but the underlying mechanisms remain to be elucidated. Based on NMR and MS spectroscopic analysis, we propose three structural characteristics found in natural products required for the suppressive activity against Aβ42 aggregation (i.e., oligomerization by targeting specific amino acid residues on this protein). These characteristics include (1) catechol-type flavonoids that can form Michael adducts with the side chains of Lys16 and 28 in monomeric Aβ42 through flavonoid autoxidation; (2) non-catechol-type flavonoids with planarity due to α,β-unsaturated carbonyl groups that can interact with the intermolecular β-sheet region in Aβ42 aggregates, especially aromatic rings such as those of Phe19 and 20; and (3) carboxy acid derivatives with triterpenoid or anthraquinoid that can generate a salt bridge with basic amino acid residues such as Lys16 and 28 in the Aβ42 dimer or trimer. Here, we summarize the recent body of knowledge concerning amyloidogenic inhibitors, particularly in functional food components and Kampo medicine, and discuss their application in the treatment and prevention of AD. Full article
(This article belongs to the Special Issue Amyloid Inhibitors and Modulators)
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