Small molecule-mediated co-assembly of amyloid-β oligomers reduces neurotoxicity through promoting non-fibrillar aggregation

Amyloid-β (Aβ) oligomers, particularly low molecular weight (LMW) oligomers, rather than fibrils, contribute very significantly to the onset and progression of Alzheimer''s Disease (AD). However, due to the inherent heterogeneity and metastability of oligomers, most of the conventional anti-oligomer therapies have indirectly modulated oligomers'' toxicity through manipulating Aβ self-assembly to reduce oligomer levels, which are prone to suffering from the risk of regenerating toxic oligomers from the products of modulation. To circumvent this disadvantage, we demonstrate, for the first time, rational design of rigid pincer-like scaffold-based small molecules with blood–brain barrier permeability that specifically co-assemble with LMW Aβ oligomers through directly binding to the exposed hydrophobic regions of oligomers to form non-fibrillar, degradable, non-toxic co-aggregates. As a proof of concept, treatment with a europium complex (EC) in such a structural mode can rescue Aβ-mediated dysfunction in C. elegans models of AD in vivo. This small molecule-mediated oligomer co-assembly strategy offers an efficient approach for AD treatment.

A rational design of pincer-like scaffold-based small molecule with blood-brain barrier permeability that can specifically co-assemble with low molecular weight Aβ oligomers to form non-fibrillar, degradable, non-toxic co-aggregates.     

Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer''s disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined ¹⁹F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrP^C in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer''s disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development.

A new approach combining virtual screening, ¹⁹F and STD NMR, and biochemical assays using hiPSC and targetting multiple pathways involving Aβ, PrP^C and Tau provides a more effective strategy for Alzheimer''s disease drug discovery than Aβ only approach.     

A fluorescent molecular imaging probe with selectivity for soluble tau aggregated protein

Soluble forms of aggregated tau misfolded protein, generally termed oligomers, are considered to be the most toxic species of the different assembly states that are the pathological components of neurodegenerative disorders. Therefore, a critical biomedical need exists for imaging probes that can identify and quantify them. We have designed and synthesized a novel fluorescent probe, pTP-TFE for which binding and selectivity profiles towards aggregated tau and Aβ proteins were assessed. Our results have shown pTP-TFE to be selective for early forms of soluble tau aggregates, with high affinity of dissociation constants (K_d) = 66 nM, and tenfold selectivity over mature tau fibrils. Furthermore, we found that pTP-TFE is selective for tau over Aβ aggregates and had good cell permeability. This selectivity of pTP-TFE towards early forms of aggregated tau protein ex vivo was also supported with studies on human brain tissue containing tau and Aβ pathology. To the best of our knowledge, this is the first fluorescent molecule to be reported to have this form of selectivity profile, which suggests that pTP-TFE is a unique probe candidate for imaging-based detection of early stages of Alzheimer''s disease and other tauopathies.

pTP-TFE imaging probe can distinguish soluble tau aggregated proteins from other aggregated proteins enabling earlier detection of neurodegenerative diseases.     

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-β

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer''s disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-β (Aβ) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aβ and metal-bound Aβ (metal–Aβ). Herein, we report, for the first time, that SP is capable of interacting with both Aβ and metal ions and consequently affects the aggregation of metal-free Aβ and metal–Aβ. Moreover, incubation of SP with Aβ in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aβ and metal–Aβ in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aβ and metal–Aβ aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aβ and metal–Aβ. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aβ and metal–Aβ is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

The reactivity of sphingosine and acetylsphingosines towards both metal-free and metal-treated amyloid-β is demonstrated showing a correlation of their micellization properties.     

A hierarchical assembly strategy for near-infrared photothermal conversion: unconventional heterogeneous metalla[2]catenanes

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion. Thienothiophene and diketopyrrolopyrrole groups were selected as the D and A units, leading to two homogeneous metalla[2]catenanes with D–D–D–D and A–A–A–A stacks, respectively. By the ordered secondary assembly of homogeneous metalla[2]catenanes, two unprecedented heterogeneous D–A metalla[2]catenanes comprising an unusual mixed D–A–D–D and unconventional D–A–A–A stacks were realized by the combination of multiple noncovalent interactions, as all demonstrated by a detailed X-ray crystallographic study. Benefiting from the mixed D–A stacking modes, NIR absorption of heterogeneous D–A metalla[2]catenanes is significantly enhanced in contrast to homogeneous metalla[2]catenanes. Thanks to the enhanced NIR absorption and the fluorescence quenching effect from half-sandwich organometallic fragments, heterogeneous D–A metalla[2]catenanes displayed high-performance NIR photothermal conversion properties (η = 27.3%).

Herein, we report a hierarchical assembly strategy for constructing heterogeneous half-sandwich organometallic D–A (D = π-donor, A = π-acceptor) interlocked structures, and their application in near-infrared (NIR) photothermal conversion.     

An explicitly designed paratope of amyloid-β prevents neuronal apoptosis in vitro and hippocampal damage in rat brain

Synthetic antibodies hold great promise in combating diseases, diagnosis, and a wide range of biomedical applications. However, designing a therapeutically amenable, synthetic antibody that can arrest the aggregation of amyloid-β (Aβ) remains challenging. Here, we report a flexible, hairpin-like synthetic paratope (SP1, ∼2 kDa), which prevents the aggregation of Aβ monomers and reverses the preformed amyloid fibril to a non-toxic species. Structural and biophysical studies further allowed dissecting the mode and affinity of molecular recognition events between SP1 and Aβ. Subsequently, SP1 reduces Aβ-induced neurotoxicity, neuronal apoptosis, and ROS-mediated oxidative damage in human neuroblastoma cells (SH-SY5Y). The non-toxic nature of SP1 and its ability to ameliorate hippocampal neurodegeneration in a rat model of AD demonstrate its therapeutic potential. This paratope engineering module could readily implement discoveries of cost-effective molecular probes to nurture the basic principles of protein misfolding, thus combating related diseases.

Herein, the therapeutic potentials of an explicitly designed peptide probe are systematically illuminated in vitro and in vivo against Aβ aggregation. The probe demonstrates remarkable potency for attenuating neurotoxicity and hippocampal damage.     

Thermodynamics and kinetics of the amyloid-β peptide revealed by Markov state models based on MD data in agreement with experiment

The amlyoid-β peptide (Aβ) is closely linked to the development of Alzheimer''s disease. Molecular dynamics (MD) simulations have become an indispensable tool for studying the behavior of this peptide at the atomistic level. General key aspects of MD simulations are the force field used for modeling the peptide and its environment, which is important for accurate modeling of the system of interest, and the length of the simulations, which determines whether or not equilibrium is reached. In this study we address these points by analyzing 30-μs MD simulations acquired for Aβ40 using seven different force fields. We assess the convergence of these simulations based on the convergence of various structural properties and of NMR and fluorescence spectroscopic observables. Moreover, we calculate Markov state models for the different MD simulations, which provide an unprecedented view of the thermodynamics and kinetics of the amyloid-β peptide. This further allows us to provide answers for pertinent questions, like: which force fields are suitable for modeling Aβ? (a99SB-UCB and a99SB-ILDN/TIP4P-D); what does Aβ peptide really look like? (mostly extended and disordered) and; how long does it take MD simulations of Aβ to attain equilibrium? (at least 20–30 μs). We believe the analyses presented in this study will provide a useful reference guide for important questions relating to the structure and dynamics of Aβ in particular, and by extension other similar disordered proteins.

The convergence of MD simulations is tested using varying measures for the intrinsically disordered amyloid-β peptide (Aβ). Markov state models show that 20–30 μs of MD is needed to reliably reproduce the thermodynamics and kinetics of Aβ.     

Target-driven supramolecular self-assembly for selective amyloid-β photooxygenation against Alzheimer's disease

Photo-oxygenation of β-amyloid (Aβ) has been considered an efficient way to inhibit Aβ aggregation in Alzheimer''s disease (AD). However, current photosensitizers cannot simultaneously achieve enhanced blood–brain barrier (BBB) permeability and selective photooxygenation of Aβ, leading to poor therapeutic efficacy, severe off-target toxicity, and substandard bioavailability. Herein, an Aβ target-driven supramolecular self-assembly (PKNPs) with enhanced BBB penetrability and switchable photoactivity is designed and demonstrated to be effective in preventing Aβ aggregation in vivo. PKNPs are prepared by the self-assembly of the Aβ-targeting peptide KLVFF and an FDA-approved porphyrin derivative (5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin). Due to the photothermal effect of PKNPs, the BBB permeability of PKNPs under irradiation is 8.5-fold higher than that of porphyrin alone. Moreover, upon selective interaction with Aβ, PKNPs undergo morphological change from the spherical to the amorphous form, resulting in a smart transformation from photothermal activity to photodynamic activity. Consequently, the disassembled PKNPs can selectively oxygenate Aβ without affecting off-target proteins (insulin, bovine serum albumin, and human serum albumin). The well-designed PKNPs exhibit not only improved BBB permeability but also highly selective Aβ photooxygenation. Furthermore, in vivo experiments demonstrate that PKNPs can alleviate Aβ-induced neurotoxicity and prolong the life span of the commonly used AD transgenic Caenorhabditis elegans CL2006. Our work may open a new path for using supramolecular self-assemblies as switchable phototheranostics for the selective and effective prevention of Aβ aggregation and related neurotoxicity in AD.

Photo-oxygenation of β-amyloid (Aβ) has been considered an efficient way to inhibit Aβ aggregation in Alzheimer''s disease (AD). We present the first example of Aβ-responsive photodynamic therapy to treatment of AD by using PKNPs self-assemblies.     

Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry,microscopy, kinetic and microfluidic analyses

The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ₄₂ peptide in Alzheimer''s disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophysical techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ₄₂ amyloids. Kinetic analysis further corroborates that the surfaces available for the Aβ₄₂ secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ₄₂ fibrils is validated by a microfluidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.

Templating mechanism of S100A9 amyloids on Aβ fibrillar surfaces during amyloid co-aggregation process was revealed by synergy of biophysical methods including charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses.     

Metal-chelating benzothiazole multifunctional compounds for the modulation and 64Cu PET imaging of Aβ aggregation

While Alzheimer''s Disease (AD) is the most common neurodegenerative disease, there is still a dearth of efficient therapeutic and diagnostic agents for this disorder. Reported herein are a series of new multifunctional compounds (MFCs) with appreciable affinity for amyloid aggregates that can be potentially used for both the modulation of Aβ aggregation and its toxicity, as well as positron emission tomography (PET) imaging of Aβ aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Aβ oligomerization into the formation of less toxic amyloid fibrils. In addition, HYR-16 can also alleviate the formation of reactive oxygen species (ROS) caused by Cu²⁺ ions through Fenton-like reactions. Secondly, these MFCs can be easily converted to PET imaging agents by pre-chelation with the ⁶⁴Cu radioisotope, and the Cu complexes of HYR-4 and HYR-17 exhibit good fluorescent staining and radiolabeling of amyloid plaques both in vitro and ex vivo. Importantly, the ⁶⁴Cu-labeled HYR-17 is shown to have a significant brain uptake of up to 0.99 ± 0.04 %ID per g. Overall, by evaluating the various properties of these MFCs valuable structure–activity relationships were obtained that should aid the design of improved therapeutic and diagnostic agents for AD.

A series of multifunctional compounds and their ⁶⁴Cu complexes exhibit good affinity for Aβ aggregates and can also control Aβ toxicity.     

High-efficiency dynamic sensing of biothiols in cancer cells with a fluorescent β-cyclodextrin supramolecular assembly

A unique fluorescent supramolecular assembly was constructed using coumarin-modified β-cyclodextrin as a reversible ratiometric probe and an adamantane-modified cyclic arginine–glycine–aspartate peptide as a cancer-targeting agent via host–guest inclusion complexation. Importantly, the coumarin-modified β-cyclodextrin not only showed higher sensitivity than the parent coumarin derivatives owing to the presence of numerous hydroxyl groups on the cyclodextrin but also provided a hydrophobic cavity for encapsulation of a cancer-targeting agent. The assembly showed a reversible and fast response to biothiols with a micromolar dissociation constant, as well as outstanding cancer cell permeability, which can be used for high-efficiency real-time monitoring of biothiols in cancer cells. This supramolecular assembly strategy endows the fluorescent probe with superior performance for dynamic sensing of biothiols.

A unique fluorescent supramolecular assembly was constructed from coumarin-modified β-cyclodextrin and an adamantane-modified cyclic arginine–glycine–aspartate peptide for high-efficiency real-time monitoring of biothiols in cancer cells.     

Activating mechanosensitive channels embedded in droplet interface bilayers using membrane asymmetry

Droplet microcompartments linked by lipid bilayers show great promise in the construction of synthetic minimal tissues. Central to controlling the flow of information in these systems are membrane proteins, which can gate in response to specific stimuli in order to control the molecular flux between membrane separated compartments. This has been demonstrated with droplet interface bilayers (DIBs) using several different membrane proteins combined with electrical, mechanical, and/or chemical activators. Here we report the activation of the bacterial mechanosensitive channel of large conductance (MscL) in a dioleoylphosphatidylcholine:dioleoylphosphatidylglycerol DIB by controlling membrane asymmetry. We show using electrical measurements that the incorporation of lysophosphatidylcholine (LPC) into one of the bilayer leaflets triggers MscL gating in a concentration-dependent manner, with partial and full activation observed at 10 and 15 mol% LPC respectively. Our findings could inspire the design of new minimal tissues where flux pathways are dynamically defined by lipid composition.

Electrophysiology shows asymmetric lysophosphatidylcholine-containing DIBs trigger mechanosensitive channel gating, enabling user-designed, autonomous flux pathways in droplet networks.     

Modification of amyloid-beta peptide aggregation via photoactivation of strained Ru(ii) polypyridyl complexes

Alzheimer''s disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aβ) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aβ peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1–3) alters the aggregation profile of the Aβ peptide. Photoactivation of Ru1–3 results in the loss of a 6,6′-dimethyl-2,2′-bipyridyl (6,6′-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aβ peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2′-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aβ peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1–3 in the presence of pre-formed Aβ_1–42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1–3 in the presence of either monomeric or fibrillar Aβ_1–42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.

Photoactivation of a series of Ru(ii) polypyridyl complexes leads to ligand exchange and modulation of amyloid-beta peptide aggregation of relevance to Alzheimer''s disease.     

Intermediates involved in serotonin oxidation catalyzed by Cu bound Aβ peptides

The degradation of neurotransmitters is a hallmark feature of Alzheimer''s disease (AD). Copper bound Aβ peptides, invoked to be involved in the pathology of AD, are found to catalyze the oxidation of serotonin (5-HT) by H₂O₂. A combination of EPR and resonance Raman spectroscopy reveals the formation of a Cu(ii)–OOH species and a dimeric, EPR silent, Cu₂O₂ bis-μ-oxo species under the reaction conditions. The Cu(ii)–OOH species, which can be selectively formed in the presence of excess H₂O₂, is the reactive intermediate responsible for 5-HT oxidation. H₂O₂ produced by the reaction of O₂ with reduced Cu(i)–Aβ species can also oxidize 5-HT. Both these pathways are physiologically relevant and may be involved in the observed decay of neurotransmitters as observed in AD patients.

The mononuclear copper hydroperoxo species (Cu(ii)–OOH) of Cu–Aβ is the active oxidant responsible for serotonin oxidation by Cu–Aβ in the presence of physiologically relevant oxidants like O₂ and H₂O₂, which can potentially cause oxidative degradation of neurotransmitters, a marker of Alzheimer''s disease.     

Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer''s disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown. We have developed a human Aβ_1–42 analogue (Aβ^pH) that exhibits green fluorescence upon internalization into the acidic organelles of cells but is non-fluorescent at physiological pH. This allowed us to image, for the first time, glial uptake of Aβ^pH in real time in live animals. We find that microglia phagocytose more Aβ^pH than astrocytes in culture, in brain slices and in vivo. Aβ^pH can be used to investigate the phagocytic mechanisms responsible for removing Aβ from the extracellular space, and thus could become a useful tool to study Aβ clearance at different stages of AD.

Glial cell phagocytosis of pH-dependent amyloid-β, Aβ^pH, in live and fixed cultures, brain tissue sections, retina, cortex and in live animals useful for studying function in health and disease.     

Coiled coils 9-to-5: rational de novo design of α-helical barrels with tunable oligomeric states

The rational design of linear peptides that assemble controllably and predictably in water is challenging. Short sequences must encode unique target structures and avoid alternative states. However, the non-covalent forces that stabilize and discriminate between states are weak. Nonetheless, for α-helical coiled-coil assemblies considerable progress has been made in rational de novo design. In these, sequence repeats of nominally hydrophobic (h) and polar (p) residues, hpphppp, direct the assembly of amphipathic helices into dimeric to tetrameric bundles. Expanding this pattern to hpphhph can produce larger α-helical barrels. Here, we show that pentameric to nonameric barrels are accessed by varying the residue at one of the h sites. In peptides with four L/I–K–E–I–A–x–Z repeats, decreasing the size of Z from threonine to serine to alanine to glycine gives progressively larger oligomers. X-ray crystal structures of the resulting α-helical barrels rationalize this: side chains at Z point directly into the helical interfaces, and smaller residues allow closer helix contacts and larger assemblies.

Systematic de novo design of peptides that form α-helical barrels with functionalisable central channels with a range of internal diameters.     

Reductive catalytic fractionation of pine wood: elucidating and quantifying the molecular structures in the lignin oil

In-depth structural analysis of biorefined lignin is imperative to understand its physicochemical properties, essential for its efficient valorization to renewable materials and chemicals. Up to now, research on Reductive Catalytic Fractionation (RCF) of lignocellulose biomass, an emerging biorefinery technology, has strongly focused on the formation, separation and quantitative analysis of the abundant lignin-derived phenolic monomers. However, detailed structural information on the linkages in RCF lignin oligomers, constituting up to 50 wt% of RCF lignin, and their quantification, is currently lacking. This study discloses new detailed insights into the pine wood RCF lignin oil''s molecular structure through the combination of fractionation and systematic analysis, resulting in the first assignment of the major RCF-derived structural units in the ¹H–¹³C HSQC NMR spectrum of the RCF oligomers. Specifically, β-5 γ-OH, β-5 ethyl, β-1 γ-OH, β-1 ethyl, β-β 2x γ-OH, β-β THF, and 5-5 inter-unit linkages were assigned unambiguously, resulting in the quantification of over 80% of the lignin inter-unit linkages and end-units. Detailed inspection of the native lignin inter-unit linkages and their conversion reveals the occurring hydrogenolysis chemistry and the unambiguous proof of absence of lignin fragment condensation during proper RCF processing. Overall, the study offers an advanced analytical toolbox for future RCF lignin conversion and lignin structural analysis research, and valuable insights for lignin oil valorization purposes.

In-depth structural analysis of pine wood RCF lignin discloses new detailed insights into the RCF lignin oil''s molecular structure.     

Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions

Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ_1–42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ_1–42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ_1–42 monomer. TGN4 also reduces the conformational transition of the Aβ_1–42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ_1–42 monomer, which could be valuable for the further development of new anti-Alzheimer agents.     

Template effects of vesicles in dynamic covalent chemistry

Vesicle lipid bilayers have been employed as templates to modulate the product distribution in a dynamic covalent library of Michael adducts formed by mixing a Michael acceptor with thiols. In methanol solution, all possible Michael adducts were obtained in similar amounts. Addition of vesicles to the dynamic covalent library led to the formation of a single major product. The equilibrium constants for formation of the Michael adducts are similar for all of the thiols used in this experiment, and the effect of the vesicles on the composition of the library is attributed to the differential partitioning of the library members between the lipid bilayer and the aqueous solution. The results provide a quantitative approach for exploiting dynamic covalent chemistry within lipid bilayers.

Vesicle lipid bilayers have been employed as templates to modulate the product distribution in a dynamic covalent library of Michael adducts formed by mixing a Michael acceptor with thiols.     

Catalytic asymmetric synthesis of quaternary trifluoromethyl α- to ε-amino acid derivatives via umpolung allylation/2-aza-Cope rearrangement

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement of tertiary α-trifluoromethyl α-amino acid derivatives for the preparation of a variety of quaternary α-trifluoromethyl α-amino acids in high yields with excellent enantioselectivities. The umpolung reactivity empowered by the activation of the key isatin-ketoimine moiety obviates the intractable enantioselectivity control in Pd-catalyzed asymmetric linear α-allylation. In combination with quasi parallel kinetic resolution or kinetic resolution, the generality of this method is further demonstrated by the first preparation of enantioenriched quaternary trifluoromethyl β-, γ-, δ- and ε-amino acid derivatives.

In this study, we developed an efficient Ir-catalyzed cascade umpolung allylation/2-aza-Cope rearrangement for the preparation of a variety of quaternary trifluoromethyl α-ε-amino acids in high yields with excellent enantioselectivities.