Power of Dopamine: Multifunctional Compound Assisted Conversion of the Most Risk Factor into Therapeutics of Alzheimer's Disease.

In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-ß (Aß) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aß-Cu2+ complex as Aß peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aß-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

Liposome nanoparticle conjugation and cell penetrating peptide sequences (CPPs) enhance the cellular delivery of the tau aggregation inhibitor RI-AG03.

Given the pathological role of Tau aggregation in Alzheimer's disease (AD), our laboratory previously developed the novel Tau aggregation inhibitor peptide, RI-AG03. As Tau aggregates accumulate intracellularly, it is essential that the peptide can traverse the cell membrane. Here we examine the cellular uptake and intracellular trafficking of RI-AG03, in both a free and liposome-conjugated form. We also characterize the impact of adding the cell-penetrating peptide (CPP) sequences, polyarginine (polyR) or transactivator of transcription (TAT), to RI-AG03. Our data show that liposome conjugation of CPP containing RI-AG03 peptides, with either the polyR or TAT sequence, increased cellular liposome association three-fold. Inhibition of macropinocytosis modestly reduced the uptake of unconjugated and RI-AG03-polyR-linked liposomes, while having no effect on RI-AG03-TAT-conjugated liposome uptake. Further supporting macropinocytosis-mediated internalization, a 'fair' co-localisation of the free and liposome-conjugated RI-AG03-polyR peptide with macropinosomes and lysosomes was observed. Interestingly, we also demonstrate that RI-AG03-polyR detaches from liposomes following cellular uptake, thereby largely evading organellar entrapment. Collectively, our data indicate that direct membrane penetration and macropinocytosis are key routes for the internalization of liposomes conjugated with CPP containing RI-AG03. Our study also demonstrates that peptide-liposomes are suitable nanocarriers for the cellular delivery of RI-AG03, furthering their potential use in targeting Tau pathology in AD.

Rational Design of Dual-Functionalized Gd@C82 Nanoparticles to Relieve Neuronal Cytotoxicity in Alzheimer's Disease via Inhibition of Aß Aggregation.

The accumulation of amyloid-ß (Aß) peptides is a major hallmark of Alzheimer's disease (AD) and plays a crucial role in its pathogenesis. Particularly, the structured oligomeric species rich in ß-sheet formations were implicated in neuronal organelle damage. Addressing this formidable challenge requires identifying candidates capable of inhibiting peptide aggregation or disaggregating preformed oligomers for effective antiaggregation-based AD therapy. Here, we present a dual-functional nanoinhibitor meticulously designed to target the aggregation driving force and amyloid fibril spatial structure. Leveraging the exceptional structural stability and facile tailoring capability of endohedral metallofullerene Gd@C82, we introduce desired hydrogen-binding sites and charged groups, which are abundant on its surface for specific designs. Impressively, these designs endow the resultant functionalized-Gd@C82 nanoparticles (f-Gd@C82 NPs) with high capability of redirecting peptide self-assembly toward disordered, off-pathway species, obstructing the early growth of protofibrils, and disaggregating the preformed well-ordered protofibrils or even mature Aß fibrils. This results in considerable alleviation of Aß peptide-induced neuronal cytotoxicity, rescuing neuronal death and synaptic loss in primary neuron models. Notably, these modifications significantly improved the dispersibility of f-Gd@C82 NPs, thus substantially enhancing its bioavailability. Moreover, f-Gd@C82 NPs demonstrate excellent cytocompatibility with various cell lines and possess the ability to penetrate the blood-brain barrier in mice. Large-scale molecular dynamics simulations illuminate the inhibition and disaggregation mechanisms. Our design successfully overcomes the limitations of other nanocandidates, which often overly rely on hydrophobic interactions or photothermal conversion properties, and offers a viable direction for developing anti-AD agents through the inhibition and even reversal of Aß aggregation.

LETC inhibits α-Syn aggregation and ameliorates motor deficiencies in the L62 mouse model of synucleinopathy.

Alpha-Synuclein (α-Syn) aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson's disease (PD). Here, we explored the efficacy of N,N,N',N'-tetraethyl-10H-phenothiazine-3,7-diamine dihydrochloride (LETC), a protein aggregation inhibitor, on α-Syn aggregation. In both cellular models and transgenic mice, α-Syn aggregation was achieved by the overexpression of full-length human α-Syn fused with a signal sequence peptide. α-Syn accumulated in transfected DH60.21 neuroblastoma cells and α-Syn aggregation was inhibited by LETC with an EC50 of 0.066 ± 0.047 µM. Full-length human α-Syn overexpressing Line 62 (L62) mice accumulated neuronal α-Syn that was associated with a decreased motor performance in the open field and automated home cage. LETC, administered orally for 6 weeks at 10 mg/kg significantly decreased α-Syn-positive neurons in multiple brain regions and this resulted in a rescue of movement deficits in the open field in these mice. LETC however, did not improve activity deficits of L62 mice in the home cage environment. The results suggest that LETC may provide a potential disease modification therapy in synucleinopathies through the inhibition of α-Syn aggregation.

Assays for the Screening and Characterization of Tau Aggregation Inhibitors.

Aggregation of tau protein is a pathological hallmark of Alzheimer's disease and other neurodegenerative tauopathies. Inhibition of tau aggregation may provide a method for treatment of these disorders. Methods to identify tau aggregation inhibitors (TAIs) in vitro are useful and here we describe assays for TAIs using purified recombinant tau protein fragments in a cell-free immunoassay format and in a stably transfected cell model to create a more physiological environment.

Therapeutic potential of Coumarin-polyphenolic acid hybrids in PD: Inhibition of α-Syn aggregation and disaggregation of preformed fibrils, leading to reduced neuronal inclusion formation.

This study focuses on the discovery of new potential drugs for treating PD by targeting the aggregation of α-Syn. A series of hybrids combining Coumarin and phenolic acid were designed and synthesized. Four particularly promising compounds were identified, showing strong inhibitory effects with IC50 values ranging from low micromolar to submicromolar concentrations, as low as 0.63 µM. These compounds exhibited a higher binding affinity to α-Syn residues and effectively hindered the entire aggregation process, maintaining the proteostasis conformation of α-Syn and preventing the formation of ß-sheet aggregates. This approach holds significant promise for PD prevention. Additionally, these candidate compounds demonstrated the ability to break down preformed α-Syn oligomers and fibrils, resulting in the formation of smaller aggregates and monomers. Moreover, the candidate compounds showed impressive effectiveness in inhibiting α-Syn aggregation within nerve cells, thereby reducing the likelihood of α-Syn inclusion formation resembling Lewy bodies, which highlights their potential for treating PD.

Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aß) aggregation inhibitors.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aß) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aß peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aß peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aß peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aß peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aß peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aß peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events.

BACKGROUND: Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk. METHODS: Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events. RESULTS: Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events. CONCLUSIONS: Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.

The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers.

The aggregation of α-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining α-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlorophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to α-Syn residues, demonstrating promising inhibitory activity against α-Syn aggregation in vitro, with low IC50 values (1.35 and 1.08 µM, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing α-Syn's conformation and preventing the formation of ß-sheet aggregates. They also effectively disassembled preformed α-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric α-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting α-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.

Study of Factors to Increase the Usage Rate of Generic Drugs in Platelet Aggregation Inhibitors.

To reduce pharmacy-related medical expenses, it is necessary to reduce drug costs. One way to achieve this is by increasing the usage rate of generic drugs. The purpose of this study was to identify platelet aggregation inhibitors (PAIs) that contribute to high drug costs and are sold as brand-name drugs in order to increase the usage rate of generic drugs, and to analyze the factors that affect the usage rate of generic drug. We conducted a cross-sectional study based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan (NODJ) of the Ministry of Health, Labor and Welfare and datasets containing related medical information from official statistical surveys such as the Basic Survey on Wage Structure. Monthly personal income in each prefecture were negatively correlated with outpatient out-of-hospital and outpatient in-hospital prescriptions of the PAIs clopidogrel (75 mg), cilostazol (50 mg), cilostazol (100 mg), and ticlopidine (100 mg), but not between monthly personal income and outpatient out-of-hospital prescription of ticlopidine (100 mg). For outpatient out-of-hospital prescriptions and outpatient in-hospital prescriptions, negative correlation was generally observed between the usage rate of generic drug and monthly personal income, except for ticlopidine (100 mg), which has the lowest price among the brand-name drugs. The usage rate of generic PAIs is negatively correlated with monthly personal income. Promoting the use of generic drugs among high-income earners might be necessary to further increase the usage rate of generic drug.

Know When You Are Too Many: Density-Dependent Release of Pheromones During Host Colonisation by the European Spruce Bark Beetle, Ips typographus (L.).

Individuals across various animal species communicate their presence to conspecifics. Especially phytophagous and parasitoid insects with their brood developing on limited resources rely on chemical cues, such as host-marking pheromones, to reduce intraspecific competition. Bark beetles are phytophagous insects with some species being economically and ecologically relevant forest pests. Several of them use the volatile compound verbenone to inhibit attraction and reduce intraspecific competition. However, in the Eurasian spruce bark beetle, Ips typographus (L.), temporal emission patterns did so far not quite support the putative function of verbenone as an indicator of densely colonised host trees. More importantly, it is currently unclear how well verbenone emission is actually related to colonisation density and thus intraspecific competition. Here, we inoculated Norway spruce logs with I. typographus at two defined colonisation densities in the greenhouse and measured the emission of verbenone and its precursors α-pinene and verbenol over time. Verbenone emission was 3-7 times greater from colonised logs compared to decaying logs without beetles during the major part of larval development. Furthermore, our data supports the quantitative hypothesis, that the termination of attack on a tree is mediated by a cessation of the release of verbenol and continuous emission of verbenone. The latter is most likely a passively produced host-marking cue reflecting the actual density of conspecifics since per-beetle emission was unaffected by colonisation density. These findings shed new light on the regulation of bark beetle mass aggregations, which are currently causing previously unseen economic damages in temperate forests.

Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.

Immunoglobulin light chain amyloidosis (AL) is a cancer of plasma cells that secrete unstable full-length immunoglobulin light chains. These light chains misfold and aggregate, often with aberrant endoproteolysis, leading to organ toxicity. AL is currently treated by pharmacological elimination of the clonal plasma cells. Since it remains difficult to completely kill these cells in the majority of patients, we seek a complementary drug that inhibits light chain aggregation, which should diminish organ toxicity. We discovered a small-molecule binding site on full-length immunoglobulin light chains by structurally characterizing hit stabilizers emerging from a high-throughput screen seeking small molecules that protect full-length light chains from conformational excursion-linked endoproteolysis. The x-ray crystallographic characterization of 7 structurally distinct hit native-state stabilizers provided a structure-based blueprint, reviewed herein, to design more potent stabilizers. This approach enabled us to transform hits with micromolar affinity into stabilizers with nanomolar dissociation constants that potently prevent light chain aggregation.

Site-specific amino acid D-isomerization of Tau R2 and R3 peptides changes the fibril morphology, resulting in attenuation of Tau aggregation inhibitor potency.

Tau, a microtubule-binding protein, is a major component of neurofibrillary tangles in the brains of Alzheimer's disease patients. Tau aggregation following fibril formation induces Alzheimer's disease pathogenesis. The accumulation of D-isomerized amino acids in proteins that occurs in several tissues with aging is thought to be implicated in age-related diseases. D-isomerized Asp accumulation has also been found in Tau in neurofibrillary tangles. We previously demonstrated the effects of D-isomerization of Asp within microtubule-binding repeat peptides of Tau, Tau R2, and R3 on the rates of structural transition and fibril formation. Here, we investigated the potency of Tau aggregation inhibitors on fibril formation of wild-type Tau R2 and R3 peptides and D-isomerized Asp-containing Tau R2 and R3 peptides. D-isomerization of Asp within Tau R2 and R3 peptides attenuated the potency of inhibitors. We next investigated the fibril morphology of D-isomerized Asp-containing Tau R2 and R3 peptides by electron microscopy. D-isomerized Asp-containing Tau R2 and R3 fibrils showed significantly different fibril morphology from that of wild-type peptides. Our results indicate that D-isomerization of Asp within Tau R2 and R3 peptides affects fibril morphology, resulting in attenuation of the potency of Tau aggregation inhibitors.

Tau-aggregation inhibitors derived from Streptomyces tendae MCCC 1A01534 protect HT22 cells against okadaic acid-induced damage.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by tau aggregating into neurofibrillary tangles. Targeting tau aggregation is one of the most critical strategies for AD treatment and prevention. Herein, a high-throughput screening of tau-aggregation inhibitors was performed by thioflavin T (ThT) fluorescence assay and tauR3 peptides. According to bioactivity-guided isolation, homoprejadomycin (1) was obtained from the marine bacterium Streptomyces tendae MCCC 1A01534. Two new stable derivatives, 2 and 3, were yielded in a one-step reaction. By ThT assay, transmission electron microscopy, and circular dichroism, we demonstrated that the angucyclinones 2 and 3 inhibited tau aggregation and disaggregated tau fibrils. In the presence of 2, native tauR3 peptides maintained the disorder conformation, whereas the tauR3 aggregates reduced ß-sheet structures. And compound 2 was confirmed to inhibit the aggregation of full-length 2N4R tau protein. Furthermore, 2 with low cytotoxicity protected HT22 cells from okadaic acid-induced damage by suppressing tau aggregates. These results indicated that 2 was a promising lead structure with tau therapeutic potency for AD treatment.

Inhibition of amyloid-ß(16-22) aggregation by polyphenols using replica permutation with solute tempering molecular dynamics simulation.

Aggregates of amyloid-ß (Aß) peptides are thought to cause Alzheimer's disease. Polyphenolic compounds are known to inhibit Aß aggregation. We applied replica permutation with solute tempering (RPST) to the system of Aß fragments, Aß(16-22), and polyphenols to elucidate the mechanism of inhibition of Aß aggregation. The RPST molecular dynamics simulations were performed for two polyphenols, myricetin (MYC) and rosmarinic acid (ROA). Two Aß fragments were distant, and the number of residues forming the intermolecular ß-sheet was reduced in the presence of MYC and ROA compared with that in the absence of polyphenols. MYC was found to interact with glutamic acid and phenylalanine of Aß fragments. These interactions induce helix structure formation of Aß fragments, making it difficult to form ß-sheet. ROA interacted with glutamic acid and lysine, which reduced the hydrophilic interaction between Aß fragments. These results indicate that these polyphenols inhibit the aggregation of Aß fragments with different mechanisms.

REMD Simulations of Full-Length Alpha-Synuclein Together with Ligands Reveal Binding Region and Effect on Amyloid Conversion.

Alpha-synuclein is a key protein involved in the development and progression of Parkinson's disease and other synucleinopathies. The intrinsically disordered nature of alpha-synuclein hinders the computational screening of new drug candidates for the treatment of these neurodegenerative diseases. In the present work, replica exchange molecular dynamics simulations of the full-length alpha-synuclein together with low-molecular ligands were utilized to predict the binding site and effect on the amyloid-like conversion of the protein. This approach enabled an accurate prediction of the binding sites for three tested compounds (fasudil, phthalocyanine tetrasulfonate, and spermine), giving good agreement with data from experiments by other groups. Lots of information about the binding and protein conformational ensemble enabled the suggestion of a putative effect of the ligands on the amyloid-like conversion of alpha-synuclein and the mechanism of anti- and pro-amyloid activity of the tested compounds. Therefore, this approach looks promising for testing new drug candidates for binding with alpha-synuclein or other intrinsically disordered proteins and at the same time the estimation of the effect on protein behavior, including amyloid-like aggregation.

Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.

BACKGROUND: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD). OBJECTIVES: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY). DESIGN: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase. SETTING: 76 clinical research sites in North America and Europe. PARTICIPANTS: 545 patients with probable AD or MCI-AD in the final version of the protocol. INTERVENTION: Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose. MEASUREMENTS: Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography. RESULTS: 446 participants are expected to complete the 12-month placebo-controlled phase in March 2022. CONCLUSIONS: If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

Chemical analysis of amyloid ß aggregation inhibitors derived from Geranium thunbergii.

Amyloid ß (Aß) aggregates in the brains of patients with Alzheimer's disease (AD) and accumulates via oligomerization and subsequent fiber elongation processes. These toxicity-induced neuronal damage and shedding processes advance AD progression. Therefore, Aß aggregation-inhibiting substances may contribute to the prevention and treatment of AD. We screened for Aß42 aggregation inhibitory activity using various plant extracts and compounds, and found high activity for a Geranium thunbergii extract (EC50 = 18 µg/mL). Therefore, we screened for Aß42 aggregation inhibitors among components of a G. thunbergii extract and investigated their chemical properties in this study. An active substance was isolated from the ethanol extract of G. thunbergii based on the Aß42 aggregation inhibitory activity as an index, and the compound was identified as geraniin (1) based on spectral data. However, although geraniin showed in vitro aggregation-inhibition activity, no binding to Aß42 was observed via saturation transfer difference-nuclear magnetic resonance (STD-NMR). In contrast, the hydrolysates gallic acid (2) and corilagin (5) showed aggregation-inhibiting activity and binding was observed via STD-NMR. Therefore, the hydrolysates produced under the conditions of the activity test may contribute to the Aß42 aggregation-inhibition activity of G. thunbergii extracts. Geraniin derivatives may help prevent and treat AD.

Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils.

α-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction with α-Syn protein residues. Some compounds have shown high α-Syn aggregation inhibitory activities in vitro with IC50 down to 0.64 µM. The inhibition goes throughout the aggregation process from the lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing ß-sheets aggregation, especially in the lag phase. In addition, the inhibitors present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the ß-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril and yielding a complex system with aggregates of different sizes and monomers. The inhibitors, which could penetrate the blood-brain barrier, are expected to develop into the drug candidates for PD targeting α-Syn aggregation.

Hybrids of polyphenolic acids and xanthone, the potential preventive and therapeutic effects on PD: Design, synthesis, in vitro anti-aggregation of α-synuclein, and disaggregation against the existed α-synuclein oligomer and fibril.

The misfolding and aggregation of α-Syn are the central mechanism linking and facilitating the other pathological mechanisms of PD. Maintaining α-Syn proteostasis by suitable inhibitors is an effective means to prevent PD. Disintegrating the neurotoxic oligomers and fibrils into the normal functional α-Syn by inhibitors is a more efficient way for PD treatment. This work synthesized two series hybrids of polyphenolic acids and xanthone. The hybrids possess a sheet-like conjugated skeleton and higher binding energies with α-Syn residues. Some compounds present well α-Syn aggregation inhibitory activities in vitro (IC50 down to 2.58 µM). The inhibitory action goes throughout the aggregation process from lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing ß-sheets aggregation. The candidate compounds with appropriate LogP values (2.02-3.11) present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the ß-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril, yielding a complex system with aggregates of different sizes and monomers.