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Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Her...
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... our laboratory, we identified and developed compounds that specifically and directly eliminate toxic A oligomers. Previously, we described the properties of our lead compound D3 (Table 1). D3 consists of twelve D-enantiomeric amino acid residues and has been identified by mirror image phage display [5][6][7][8][9]. ...
Citations
... Schartmann et al. compared previously reported D3 and its derivatives, such as ANK6, with its tandem version (tANK6) and its head-to-tail cyclized isoform (cANK6r) against Ab 1-42 aggregation inhibition. The peptide efficiency and pharmacokinetic availability of D3 and its derivatives increased due to head-to-tail cyclization [47]. Previously, D3 was a 12-mer D-enantiomeric peptide identified by the mirror image phage display technique. ...
... Cell viability study showed that ANK6, tANK6, or cANK6r were better than D3. Preclinical pharmacokinetic studies of the three all-D-peptides in wild-type mice showed good blood-brain barrier permeability, with cANK6r yielding the highest levels in the brain [47]. In 2018, Solarski et al. tested somatostatin, a neuropeptide hormone, as an inhibitor of Ab 1-42 fibrillogenesis. ...
The pathological hallmark of many amyloid diseases is the aggregation and deposition of soluble proteins into toxic insoluble fibrils in various tissues. Without any definite cure for these proteinopathies, researchers have explored small molecules, antibodies, peptides, nanomaterials etc., as potential agents interacting with different conformational species of amyloid-forming proteins. Mainly, amyloid fibrillation inhibitors in the form of cyclic peptides (CPs) (based on amyloid and non-amyloid-forming protein sequences) show remarkable anti-amyloidogenic activity as well as chemical, thermal, and proteolytic stability over their linear counterparts. Furthermore, some 'add-on' attributes include ease of synthesis, amenability for chemical modification, precise and tight binding (high specificity) to target peptides, and biocompatibility. This article highlights the design, synthesis, bioactivity, and mechanistic evaluation of rationally designed CPs inhibitors against amyloid systems. This review also discusses the dual role of nanoparticles as inhibitors of amyloid fibrillation and as carriers for the delivery of therapeutic molecules across the blood–brain barrier. Thus, combining CPs and nanoparticles could represent ‘next-generation therapeutics’ for amyloid diseases.
Graphical abstract
... One of the major signature characteristics of AD is A protein aggregation. Consequently, the formation, aggregation, and degradation of A have become major targets in research and development of drugs and therapeutic agents for AD [15,16]. In this regard, substances with high potency in inhibiting the aggregation or enhancing the degradation of A are considered useful in the search for the prevention and/or treatment of AD [3,14,17]. ...
BACKGROUND: Antioxidant peptides have gained attention as potential therapeutic agents for Alzheimer’s disease (AD). The gut microbiota is also increasingly being recognized as central to AD progression and a potential therapeutic target for the disease. OBJECTIVE: Using a recently-identified antioxidant pentapeptide (Trp-Pro-Pro-Lys-Asn, WN5), we sort to test the hypothesis that dietary components could target the microbiota to inhibit Aβ aggregation and relieve AD-related cognitive impairments. METHOD: An Aβ42 aggregation cell model was employed to predict the ability of WN5 to inhibit Aβ aggregation. APP/PS1 mice were then used to explore the learning and memory-improving capacity of WN5 by targeting the gut microbiota. RESULTS: WN5 dose-dependently attenuated cellular Aβ-aggregation. Oral administration of WN5 (WN5_G) was associated with decreased microbial diversity and tended to impact the abundance of several major bacterial species associated with AD. The observed microbiota changes were significantly associated with reduced hippocampal Aβ aggregation (17.6±0.71 for WN5_G and 25.4±1.7 for the control group; p < 0.009) and improved cognitive performance. However, these observations were absent when WN5 was administered intraperitoneally (WN5_Ip). CONCLUSION: The results from this preliminary study suggested that WN5 could be useful in ameliorating AD-related symptoms via the gut-brain-axis and further emphasize the significance of the gut microbiota in AD.
... PRI-002 is a peptide with 12 D-amino acid residues. It has recently completed Phase 1 and has a similar mode of action to GAL-201 in fighting toxic Aβ oligomers, including the self-propagating detoxification mechanism [51]. The molecule can be administered orally, however, with a low bioavailability typical of peptide drugs. ...
Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.
... Mutierte Tau-Würmer zeigen morphologische Veränderungen in Neuronen, die an neuronale Alterung erinnern (Pir et al. 2016). Dieses Modell dient als Vorstufe der in vivo-Untersuchungen, um die Auswirkungen des therapeutischen Peptids ISAD1 zu testen, bevor Studien an transgenen AD-Mäusen durchgeführt werden.Die Entwicklung von Tandemliganden, wie beispielsweise heterodimere Peptide, in der AD-Therapie erlangt immer mehr Bedeutung und ist bereits in mehreren Studien beschrieben wordenLeithold et al. 2016;Schartmann et al. 2018). Der Grundgedanke bei dem Design von Tandempeptiden ist, dass multivalente D-Peptide ihre multivalenten Zielmoleküle mit erhöhter Effizienz angreifen können. ...
Aktuell leiden etwa 55 Millionen Menschen weltweit an einer Demenz. Die Alzheimersche Demenz (AD) ist die häufigste Demenzursache, auf die schätzungsweise 60 % bis 80 % der Fälle fallen. Die AD ist eine fortschreitende neurodegenerative Störung, die hauptsächlich ältere Erwachsene betrifft. Es wird angenommen, dass die neurologischen Veränderungen der AD Jahre oder Jahrzehnte vor dem Auftreten von Symptomen einsetzten. Sie beginnt mit Veränderungen im Gehirn, die von den Betroffenen zunächst nicht bemerkt werden. Erst nach Jahren der Hirnveränderungen kommt es zu spürbaren Symptomen wie Gedächtnisverlust und Sprachproblemen. Die Symptome treten auf, weil Nervenzellen in Teilen des Gehirns, die für die Wahrnehmung, das Lernen und das Gedächtnis (kognitive Funktionen) zuständig sind, geschädigt oder zerstört wurden. Mit dem Fortschreiten der Krankheit breitet sich die Pathologie in weiteren Teilen des Gehirns aus, bis es Betroffenen schließlich nicht mehr möglich ist, grundlegende Körperfunktionen wie Gehen und Schlucken auszuführen. Im Endstadium der Erkrankung werden die Betroffenen bettlägerig und benötigen rund um die Uhr Pflege. Die Hauptpathologien der AD sind die Anhäufung des Proteinfragments Beta-Amyloid (sogenannte Aβ-Plaques) außerhalb der Nervenzellen im Gehirn und Ablagerungen des Tau-Proteins (sogenannte Tau-Tangles) innerhalb der Nervenzellen. Diese Veränderungen gehen mit dem Absterben von Nervenzellen und der Beschädigung von Hirngewebe einher, die wiederum zu Entzündungen und zum Rückgang des Hirnvolumens (Atrophie) führen. Eine sichere Diagnose kann aktuell nur nach dem Tod gestellt werden und keine der heute verfügbaren Medikamente für AD verlangsamen oder stoppen die Schädigung und Zerstörung von Nervenzellen, sodass lediglich eine symptomatische Behandlung verfügbar ist. Viele potenzielle therapeutische Substanzen für AD, die mit der Aβ-Pathologie in Zusammenhang stehen, wurden erfolgreich in präklinischen Modellen getestet, aber die meisten von ihnen scheiterten in klinischen Studien aufgrund von mangelndem therapeutischem Nutzen oder unerwünschten Nebenwirkungen. Die US-Arzneimittelbehörde FDA hat Aducanumab, ein Aβ-Antikörper, als einziges Medikament zugelassen, das möglicherweise das Fortschreiten der AD verlangsamen kann, dennoch ist die Zulassung umstritten und die Wirksamkeit von Aducanumab muss in weiteren Studien nachgewiesen werden. Von der Europäischen Arzneimittel-Agentur (EMA) erhielt Aducanumab aufgrund von nicht nachgewiesener Wirksamkeit und möglichen schwerwiegenden Nebenwirkungen keine Zulassung. Zahlreiche Studien deuten darauf hin, dass die Tau-Pathologie im engeren Zusammenhang mit dem Fortschreiten der Krankheit und den klinischen Symptomen steht, was zu einer verstärkten Erforschung von Tau-assoziierten Wirkstoffen geführt hat. Die Tau-Pathologie tritt nicht nur bei der AD auf, sondern auch bei anderen neurologischen Erkrankungen, den sogenannten Tauopathien, wodurch sich der Anwendungsbereich einer therapeutischen Substanz erweitern lassen könnte. Tau ist ein intrazellulär exprimiertes Protein, das an der Stabilisierung der Mikrotubuli und am axonalen Transport beteiligt ist. Unter pathologischen Bedingungen löst sich Tau von den Mikrotubuli, wodurch diese zerfallen und das ungebundene Tau kann unter Umständen zu Oligomeren oder gepaarten helikalen Filamenten (PHFs) aggregieren. Die zwei Hexapeptid-Sequenzen PHF6 (VQIVYK) und PHF6* (VQIINK) wurden als wesentliche Antreiber der Tau-Aggregation identifiziert. Weiterhin gibt es viele Hinweise auf das Vorhandensein extrazellulärer Tau-Aggregate und ihre Rolle bei der Ausbreitung der Tau-Pathologie. Diese Tatsache verdeutlicht, dass die extrazelluläre und intrazelluläre Behandlung bei der Krankheitsprävention gleich wichtig sein könnte. Es sind eine Vielzahl von Tau-Aggregationsinhibitoren beschrieben, darunter Methylenblau (LTMX), was bereits in mehreren klinischen Studien getestet wurde. Die Verwendung von kleinen D-Aminosäure (AS)-haltigen Peptiden (im nachfolgenden D-Peptide genannt) zur Verhinderung der pathologischen Aggregation und Verbreitung von Tau könnte eine Alternative zu anderen chemischen Substanzen darstellen. D-Peptide sind nachweislich proteasestabil und weniger immunogen als L-Peptide, was sie für in vivo-Anwendungen geeignet macht. Daher war das Ziel dieser Arbeit, neuartige therapeutische D-Peptide als Inhibitoren der Tau-Fibrillisation zu entwickeln. Mithilfe einer Phagen-Display-Selektion gegen das Volllänge Tau-Protein (TauFL) wurde ein neuartiges Tau-bindendes L-Peptid selektioniert und seine D-Peptid Version ISAD1 bzw. seine retro-inverse Form ISAD1rev synthetisiert. Mittels Thioflavin-Test (ThT), einem Fluoreszenzfarbstoff der spezifisch an die in Tau-Fibrillen gebildeten amyloiden β-Faltblattstrukturen bindet, wurden die Inhibitorischen Eigenschaften der D-Peptide auf die Tau-Fibrillisation untersucht. Die hier beschriebenen neuen D-Peptide inhibierten interessanterweise nicht nur die Aggregation von TauFL, sondern auch die Fibrillisation von krankheitsrelevanten Tau-Mutationsformen anderer Tauopathien, was den D-Peptiden einen erweiterten Anwendungsbereich verleiht. Während ISAD1rev für die Tau-Aggregation nur mäßig geeignete inhibitorische Eigenschaften aufwies, ergaben sich für ISAD1 vielversprechendere therapeutische Eigenschaften. Zusätzlich wurden im ELISA die Bindeeigenschaften der D-Peptide an verschiedene Tau-Isoformen und Tau-Konformere getestet. Durch die Verwendung von unterschiedlichen Tau-Isoformen wurde PHF6 als eine Bindestelle von ISAD1 identifiziert. Eine Kknformer-spezifische Bindung der D-Peptide an nicht-fibrilliertes Tau bzw. Tau-Fibrillen wurde nicht festgestellt. Nach der näheren Untersuchung des Mechanismus der Inhibition mittels Dynamischer Lichtstreuung (DLS) wurde herausgefunden, dass die D-Peptide ISAD1 und ISAD1rev die Bildung von großen, hochmolekularen Tau-Aggregaten induzieren, denen die typische ThT-negative β-Faltblatt-Konformation herkömmlicher Tau-Aggregate fehlte. Aufgrund dieser Tatsache wurde angenommen, dass es sich dabei um mutmaßliche amorphe Aggregate handeln könnte. Die Aufnahme der D-Peptide in neuronale Zellen ist als späteres AD-Therapeutikum essentiell. In Zellkulturexperimenten konnte die Aufnahme von ISAD1 und ISAD1rev von neuronalen Zellen anhand der Tau-exprimierenden Zellline N2a-TauRDΔK bestätigt werden. In weiteren Zellkulturuntersuchungen zur Zytotoxizität der D-Peptide wurden nach der Inkubation mit den D-Peptiden keine Beeinträchtigungen der Lebensfähigkeit oder der metabolischen Aktivität festgestellt. Die in den DLS-Messungen detektierten hochmolekularen mutmaßlichen Tau-Peptid-Aggregaten lösten nachweislich keine zytotoxischen Effekte bei neuronalen Zellen aus. Zusätzlich konnte gezeigt werden, dass die D-Peptide zu einer Detoxifizierung intrazellulärer Tau-Fibrillen führten, indem sie vermutlich die toxischen Tau-Aggregate in eine nicht-toxische hochmolekulare Form überführen. Zusammenfassend lässt sich sagen, dass die neuartigen D-Peptide die Fibrillenbildung von Tau und verschiedenen Tau-Mutationsformen inhibieren und die toxischen Wirkungen von Tau-Fibrillen verhindern, indem sie die Bildung herkömmlicher Fibrillen verhindern. Diese Forschungsergebnisse machen unsere Peptide zu einem potenziellen therapeutischen Molekül zur Verhinderung der Tau-Pathologie bei AD und anderen Tau-assoziierten Krankheiten. Die Untersuchung der Durchlässigkeit der Blut-Hirn-Schranke (BHS), der detaillierte Wirkmechanismus und das volle therapeutisches Potenzial der D-Peptide muss in künftigen in vivo-Behandlungsstudien nachgewiesen werden. Die D-Peptide, die in diesem Projekt entwickelt wurden, haben das Potenzial, sowohl intrazellulär als auch extrazellulär zu wirken und somit die Verbreitung der toxischen Tau-Spezies in verschiedenen Hirnregionen, aufzuhalten. Ein zukünftiger Therapieansatz der AD sollte die Protein-Fehlfaltung, Protein-Aggregation und die Verbreitung der löslichen toxischen Einheiten berücksichtigen. Das D-Peptid ISAD1 könnte nach allen Erkenntnissen ein vielversprechender Wirkstoffkandidat im Kampf gegen AD sein.
... Peptides or peptioide-based compounds were able to bind to the monomers and stop oligomerisation (Fig. 2). 27,28 Competitors for binding at the oligomerisation step that usually show good inhibition are peptides, (e.g. RVV-V, KLVFF, D-GABA-FPLIAIMA). ...
Alzheimeŕs disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL), which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to Aβ-monomers. The structure-activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.
... A relatively new class of promising drug candidates are the all-D-peptides, which consist solely of D-enantiomeric amino acid residues, and which exhibit several advantages including low immunogenicity and high proteolytic stability [35][36][37]. Recently, the excellent safety and tolerability of an all-D-peptide drug candidate could be demonstrated in a clinical phase I trial [38] after demonstrating its preclinical efficacy in several Alzheimer's disease mouse models [39][40][41]. ...
Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1G93A mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1G93A mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1G93A mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1G93A mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1G93A mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment.
... In vivo, it was demonstrated that RD2D3 has a favorable pharmacokinetic profile (after intraperitoneal (i.p.) administration), high proteolytic stability and therapeutic efficacy by improving the cognitive abilities of transgenic APP Swedish/Dutch/Iowa (Tg-SwDI) AD mice [14,15]. Besides the development of linear tandem-D-peptides, a further approach for a rational drug design was the cyclization of either homo-or tandem-D-peptides [16,17]. For the cyclized tandem-D-peptide cRD2D3, a remarkably enhanced pharmacokinetic profile was found [17]. ...
... Besides the development of linear tandem-D-peptides, a further approach for a rational drug design was the cyclization of either homo-or tandem-D-peptides [16,17]. For the cyclized tandem-D-peptide cRD2D3, a remarkably enhanced pharmacokinetic profile was found [17]. Comparing the pharmacokinetic profiles of the linear and cyclic version of the D-peptide RD2D3 (RD2D3 vs. cRD2D3) after intravenous (i.v.). ...
... and intraperitoneal (i.p.) administration in C57Bl/6 wild type (WT) mice resulted in a tremendously increased terminal half-life (2.3 vs. 58 h), increased BBB penetration values and brain peptide concentrations of cRD2D3. Furthermore, for cRD2D3 a high oral bioavailability was demonstrated [17]. Both, a long half-life and high oral bioavailability are extremely advantageous for active ingredients used in the therapy of AD and qualify for daily drug administrations. ...
Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood–brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy.
... For example, serum proteins such as albumin and α1-acid glycoprotein bind CARPs, providing a reservoir of the peptide that prolongs serum half-life and potentially extending peptide therapeutic duration (Nguyen et al., 2010;Sarko et al., 2010;Schartmann et al., 2018a). Furthermore, various peptide structural modifications such as cyclization and use of D-enantiomer amino acids can enhance resistance to serum proteases, and thus improve serum stability (Leithold et al., 2016;Nguyen et al., 2010;Schartmann et al., 2018b). With regards to tissue targeting, CARPs and CARP-conjugates generally exhibit preferential distribution in kidney, liver, spleen, lung and to a lesser extent brain (Bullok et al., 2002;Delucia et al., 1993;Fawell et al., 1994;Kameyama et al., 2006;Lee & Pardridge, 2001;Nakase et al., 2012b;Sarko et al., 2010;Schwarze et al., 1999;Wunderbaldinger et al., 2002). ...
Background:
Autoimmune thyroid diseases (AITD) represent the most common autoimmune diseases. However, current therapies focus on relieving the symptoms instead of curing AITD, and new therapies to reverse the autoimmune attack on the thyroid are needed. HLA-DRβ1-Arg74 is the key HLA class II allele that triggers AITD by presenting pathogenic thyroglobulin (Tg) peptides that activate thyroid self-reactive T-cells. We hypothesized that blocking the presentation of Tg peptides to T-cells within the HLA-DRβ1-Arg74 peptide binding cleft could reverse the autoimmune response to the thyroid in AITD.
Methods:
The approach we used to block Tg peptide presentation within HLA-DRβ1-Arg74 is to design retro-inverso D-amino acid (RID) peptides that have high affinity to the HLA-DRβ1-Arg74 peptide binding pocket.
Results:
By using computational approaches and molecular dynamics simulations, we designed two RID-peptides, RT-15 and VT-15 that blocked peptide binding to recombinant HLA-DRβ1-Arg74 molecule, as well as T-cell activation in vitro. Furthermore, RT-15 and VT-15 blocked in vivo T-cell activation by thyroglobulin in humanized NOD-DR3 mice induced with experimental autoimmune thyroiditis (EAT).
Conclusions:
In summary, we discovered two RID-peptides that block thyroglobulin peptide binding to HLA-DRβ1-Arg74 and their presentation to T-cells in AITD. These findings set the stage for a personalized medicine therapeutic approach for AITD patients who carry the DRβ1-Arg74 allele. This antigen-specific therapeutic strategy can potentially be extended to other autoimmune diseases.
Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell‐ and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti‐amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry “tools” to design, develop, and discover peptide‐based molecules as anti‐amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1) the oldest and most common strategy, based on molecular recognition elements of amyloid self‐assembly, and 2) a more recent approach, based on cross‐amyloid interactions. We discuss why peptide‐based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti‐amyloid drugs as well as valuable tools for deciphering amyloid‐mediated cell damage and its link to disease pathogenesis.
