RESUMEN
Pathogenic protein aggregates, called amyloids, are etiologically relevant to various diseases, including neurodegenerative Alzheimer disease. Catalytic photooxygenation of amyloids, such as amyloid-ß (Aß), reduces their toxicity; however, the requirement for light irradiation may limit its utility in large animals, including humans, due to the low tissue permeability of light. Here, we report that Cypridina luciferin analogs, dmCLA-Cl and dmCLA-Br, promoted selective oxygenation of amyloids through chemiexcitation without external light irradiation. Further structural optimization of dmCLA-Cl led to the identification of a derivative with a polar carboxylate functional group and low cellular toxicity: dmCLA-Cl-acid. dmCLA-Cl-acid promoted oxygenation of Aß amyloid and reduced its cellular toxicity without photoirradiation. The chemiexcited oxygenation developed in this study may be an effective approach to neutralizing the toxicity of amyloids, which can accumulate deep inside the body, and treating amyloidosis.
Asunto(s)
Oxígeno , Humanos , Oxígeno/química , Oxígeno/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/química , Amiloide/metabolismo , Amiloide/química , Estructura Molecular , AnimalesRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease associated with aging, and the number of people affected is rapidly increasing. Abnormally hyperphosphorylated tau filaments and extracellular deposits of amyloid ß-peptides (Aß) fibrils are two important pathological hallmarks of AD. Currently, stopping the production of Aß and blocking its aggregation is the main strategy for the treatment of AD. Turmeric is effective in treating neurodegenerative diseases, but there is no effective way to identify active compounds from their complicated chemical compositions. Instead of using conventional extraction and separation methods with low efficiency and time-consuming, our group tried to use atomic materials in high-throughput chemical screening due to their structural characteristics and the unique advantages of surface atomic. Herein, a novel atomic zinc sites with hierarchical porous carbon (Zn-HPC) was synthesized to quickly screen potential inhibitors of Aß aggregation in turmeric. As-combined Aß@Zn-HPC demonstrates superior storage stability and high selectivity, outperforming the most reported supporters for ligand fishing. Five compounds with strong affinity on Aß@Zn-HPC were selected by high-performance liquid chromatography-hybrid linear ion trap/orbitrap mass spectrometer after incubation with turmeric extract. Finally, it was shown that curcumin and bisdemethoxycurcumin can inhibit Aß aggregation by using thioflavin-T fluorescence assay and biolayer interferometry. A new application for the accurate identification of Aß aggregation inhibitors from turmeric were developed based on the active compounds possessing binding affinity to Aß to inhibit its aggregation. The developed method could provide a promising tool for efficient drug discovery from natural product resources.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Carbono , Humanos , Porosidad , Zinc/uso terapéuticoRESUMEN
In living systems, non-equilibrium states that control the assembly-disassembly of cellular components underlie the gradual complexification of life, whereas in nonliving systems, most molecules follow the laws of thermodynamic equilibrium to sustain dynamic consistency. Little is known about the roles of non-equilibrium states of interactions between supramolecules in living systems. Here, a non-equilibrium state of interaction between supramolecular lipopolysaccharide (LPS) and Aß42, an aggregate-prone protein that causes Alzheimer's disease (AD), was identified. Structurally, Aß42 presents a specific groove that is recognized by the amphiphilicity of LPS bait in a non-equilibrium manner. Functionally, the transient complex elicits a cellular response to clear extracellular Aß42 deposits in neuronal cells. Since the impaired clearance of toxic Aß42 deposits correlates with AD pathology, the non-equilibrium LPS and Aß42 could represent a useful target for developing AD therapeutics.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Lipopolisacáridos/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos beta-Amiloides/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Lipopolisacáridos/química , Sustancias Macromoleculares/química , Sustancias Macromoleculares/metabolismo , Sustancias Macromoleculares/farmacología , Neuronas/citología , Neuronas/metabolismo , Fragmentos de Péptidos/química , Unión ProteicaRESUMEN
BACKGROUND AND PURPOSE: Aß1-42-induced neurotoxicity has been considered as a possible mechanism to aggravate the onset and progression of Alzheimer's disease (AD). In this study, we aim to determine the protective effect of DMDD on the apoptosis of SH-SY5Y cells induced by Aß1-42 and elucidate potential mechanism of DMDD's protective function in apoptosis. EXPERIMENTAL APPROACH: CCK-8, AnnexinV-FITC/PI flow cytometry, and transmission electron microscopy analysis were used to determine the protection of DMDD on Aß1-42-evoked apoptosis of SH-SY5Y cells. Cytochrome c release, JC-1 staining, and measuring the protein of Bcl-2 family by Western blot were applied to elucidate the mechanism of DMDD's protective function in apoptosis. KEY RESULTS: Three concentration of DMDD (5 µmol/L, 10 µmol/L, and 20 µmol/L) rescues the cell viability loss and apoptosis of SH-SY5Y cells cultivated in Aß1-42. The expressions of cleaved Caspase-3, -8, -9, the cytochrome c release, and mitochondrial membrane potential loss were inhibited by DMDD in Aß1-42-insulted SH-SY5Y cells. The Western blot analysis showed that DMDD pretreatment clearly downregulated the protein of Bax and upregulated Bcl-2. Moreover, the Bcl-2/Bax ratio was obviously decreased in cells only exposed to Aß1-42, but, which was suppressed by treated with DMDD. CONCLUSION AND IMPLICATIONS: DMDD attenuated the apoptosis of SH-SY5Y cells induced by Aß1-42 through reversing the Bcl-2/Bax ratio.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Apoptosis/efectos de los fármacos , Averrhoa/química , Ciclohexenos/farmacología , Medicamentos Herbarios Chinos/farmacología , Fragmentos de Péptidos/toxicidad , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Enfermedad de Alzheimer/patología , Caspasa 3/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclohexenos/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Individual Alzheimer's disease (AD) patients have been shown to have structurally distinct amyloid-ß (Aß) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aß fibril structures. Thus, the characterization of the structural dynamics of Aß could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aß and amylin, which is associated with type II diabetes, shares some common biological features with Aß, and is reported to be involved in AD.
Asunto(s)
Péptidos beta-Amiloides/química , Polipéptido Amiloide de los Islotes Pancreáticos/química , Imagen Molecular/métodos , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Microscopía de Fuerza Atómica , Agregado de Proteínas , Conformación Proteica , Estabilidad ProteicaRESUMEN
Amyloid-ß (Aß) oligomers are implicated in Alzheimer disease (AD). However, their unstable nature and heterogeneous state disrupts elucidation of their explicit role in AD progression, impeding the development of tools targeting soluble Aß oligomers. Herein parallel and anti-parallel variants of Aß(1-40) dimers were designed and synthesized, and their pathogenic properties in AD models characterized. Anti-parallel dimers induced cognitive impairments with increased amyloidogenesis and cytotoxicity, and this dimer was then used in a screening platform. Through screening, two FDA-approved drugs, Oxytetracycline and Sunitinib, were identified to dissociate Aß oligomers and plaques to monomers in 5XFAD transgenic mice. In addition, fluorescent Astrophloxine was shown to detect aggregated Aß in brain tissue and cerebrospinal fluid samples of AD mice. This screening platform provides a stable and homogeneous environment for observing Aß interactions with dimer-specific molecules.
Asunto(s)
Péptidos beta-Amiloides/química , Amiloide/química , Memoria/efectos de los fármacos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/farmacología , Animales , Dimerización , Descubrimiento de Drogas , Femenino , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos ICR , Ratones Transgénicos , Placa Amiloide/metabolismo , Placa Amiloide/patologíaRESUMEN
Amyloid ß-peptides (Aß) play a major role in the pathogenesis of Alzheimer's disease. Therefore, numerous monoclonal antibodies against Aß have been developed for basic and clinical research. The present study applied fluorescence based analytical ultracentrifugation and microscale thermophoresis to characterize the interaction between Aß42 monomers and three popular, commercially available antibodies, namely 6E10, 4G8 and 12F4. Both methods allowed us to analyze the interactions at low nanomolar concentrations of analytes close to their dissociation constants (K D) as required for the study of high affinity interactions. Furthermore, the low concentrations minimized the unwanted self-aggregation of Aß. Our study demonstrates that all three antibodies bind to Aß42 monomers with comparable affinities in the low nanomolar range. K D values for Aß42 binding to 6E10 and 4G8 are in good agreement with formerly reported values from SPR studies, while the K D for 12F4 binding to Aß42 monomer is reported for the first time.
RESUMEN
Amyloid self-assembly is linked to the pathogenesis of Alzheimer's disease (AD) and typeâ 2 diabetes (T2D), but so far, no anti-amyloid compound has reached the clinic. Macrocyclic peptides belong to the most attractive drug candidates. Herein we present macrocyclic peptides (MCIPs) designed using minimal IAPP-derived recognition elements as a novel class of nanomolar amyloid inhibitors of both Aß40(42) and IAPP or Aß40(42) alone and show that chirality controls inhibitor selectivity. Sequence optimization led to the discovery of an Aß40(42)-selective MCIP exhibiting high proteolytic stability in human plasma and human blood-brain barrier (BBB) crossing ability in a cell model, two highly desirable properties for anti-amyloid AD drugs. Owing to their favorable properties, MCIPs should serve as leads for macrocyclic peptide-based anti-amyloid drugs and scaffolds for the design of small-molecule peptidomimetics for targeting amyloidogenesis in AD or in both AD and T2D.
Asunto(s)
Amiloide/antagonistas & inhibidores , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Nanotecnología , Péptidos/química , Péptidos/farmacología , Secuencia de AminoácidosRESUMEN
Racemates often have lower solubility than enantiopure compounds, and the mixing of enantiomers can enhance the aggregation propensity of peptides. Amyloid beta (Aß) 42 is an aggregation-prone peptide that is believed to play a key role in Alzheimer's disease. Soluble Aß42 aggregation intermediates (oligomers) have emerged as being particularly neurotoxic. We hypothesized that the addition of mirror-image d-Aß42 should reduce the concentration of toxic oligomers formed from natural l-Aß42. We synthesized l- and D-Aß42 and found their equimolar mixing to lead to accelerated fibril formation. Confocal microscopy with fluorescently labeled analogues of the enantiomers showed their colocalization in racemic fibrils. Owing to the enhanced fibril formation propensity, racemic Aß42 was less prone to form soluble oligomers. This resulted in the protection of cells from the toxicity of l-Aß42 at concentrations up to 50â µm. The mixing of Aß42 enantiomers thus accelerates the formation of non-toxic fibrils.
Asunto(s)
Péptidos beta-Amiloides/síntesis química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Microscopía Confocal , Células PC12 , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Alzheimer's disease (AD) is a complicated multifactorial syndrome. Lessons have been learned through failed clinical trials that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here, we construct core-shell nanoparticles (CeNP@MnMoS4 ) targeting multiple key pathways of the AD pathogenesis, including elimination of toxic metal ions, decrease of oxidative stress, and promotion of neurite outgrowth. The SOD activity and copper removal capacity of CeNP@MnMoS4 -n (n represents the number of layers of MnMoS4 , n=1-5) was investigated in vitro. We found that CeNP@MnMoS4 -3 made an excellent balance between SOD activity and copper removal capacity. The effect of CeNP@MnMoS4 -3 on Cu(2+) -induced Aß aggregation was studied by gel electrophoresis, transmission electron microscope (TEM), and atomic force microscopy (AFM). Compared with MnMoS4 or CeNP alone, a synergistic effect was observed. Moreover, CeNP@MnMoS4 -3 promoted neurite outgrowth in a dose-dependent manner. Taken together, the results reported in this work show the potential of new multifunctional core-shell nanoparticles as AD therapeutics.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cerio/química , Manganeso/química , Nanopartículas del Metal/química , Molibdeno/química , Sulfuros/química , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Cobre/metabolismo , Humanos , Nanopartículas del Metal/uso terapéutico , Neuritas/fisiología , Estrés Oxidativo , Tamaño de la Partícula , Agregado de Proteínas , Propiedades de SuperficieRESUMEN
In our previous studies, we reported that the activity of an anti-oxidant enzyme, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) became decreased as the result of glycation in vitro and in vivo. Glycated Cu,Zn-SOD produces hydroxyl radicals in the presence of transition metals due to the formation of a Schiff base adduct and a subsequent Amadori product. This results in the site-specific cleavage of the molecule, followed by random fragmentation. The glycation of other anti-oxidant enzymes such as glutathione peroxidase and thioredoxin reductase results in a loss or decrease in enzyme activity under pathological conditions, resulting in oxidative stress. The inactivation of anti-oxidant enzymes induces oxidative stress in aging, diabetes and neurodegenerative disorders. It is well known that the levels of Amadori products and N(e)-(carboxylmethyl)lysine (CML) and other carbonyl compounds are increased in diabetes, a situation that will be discussed by the other authors in this special issue. We and others, reported that the glycation products accumulate in the brains of patients with Alzheimer's disease (AD) patients as well as in cerebrospinal fluid (CSF), suggesting that glycation plays a pivotal role in the development of AD. We also showed that enzymatic glycosylation is implicated in the pathogenesis of AD and that oxidative stress is also important in this process. Specific types of glycosylation reactions were found to be up- or downregulated in AD patients, and key AD-related molecules including the amyloid-precursor protein (APP), tau, and APP-cleaving enzymes were shown to be functionally modified as the result of glycosylation. These results suggest that glycation as well as glycosylation are involved in oxidative stress that is associated with aging, diabetes and neurodegenerative diseases such as AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Superóxido Dismutasa-1/metabolismo , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/química , Animales , Encéfalo/patología , Glicosilación , Humanos , Superóxido Dismutasa-1/química , Proteínas tau/químicaRESUMEN
The aggregation of the amyloid ß-peptide into fibrils is a complex process that involves mechanisms such as primary and secondary nucleation, fibril elongation and fibril fragmentation. Some of these processes generate neurotoxic Aß oligomers, which are involved in the development of Alzheimer's disease. Recent experimental studies have emphasized the role of the fibril as a catalytic surface for the production of highly toxic oligomers during secondary nucleation. By using molecular dynamics simulations, we show that it is the hydrophobic fibril region that causes the structural changes required for catalyzing the formation of ß-sheet-rich Aß1-42 oligomers on the fibril surface. These results reveal, for the first time, the molecular basis of the secondary nucleation pathway.
Asunto(s)
Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Multimerización de Proteína , Estructura Secundaria de Proteína , Propiedades de SuperficieRESUMEN
UNLABELLED: Essentials How the Alzheimer's disease (AD) peptide ß-amyloid (Aß) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aß triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aß-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target. SUMMARY: Background ß-Amyloid (Aß) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Aß to contribute to a prothrombotic state. Methods and results We show that Aß activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Aß as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Aß to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD.
Asunto(s)
Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/química , Factor XII/química , Trombina/química , Precursor de Proteína beta-Amiloide/química , Animales , Coagulación Sanguínea , Velocidad del Flujo Sanguíneo , Circulación Cerebrovascular , Proteína Inhibidora del Complemento C1/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrina/química , Voluntarios Sanos , Humanos , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Trombosis/sangre , Resultado del TratamientoRESUMEN
The screening of natural products in the search for new lead compounds against Alzheimer's disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic ß-amyloid fibrils. Gallic acid based gallotannins are among these polyphenols, but their antifibrillogenic activity has thus far been examined using "tannic acid", a commercial mixture of gallotannins and other galloylated glucopyranoses. The first total syntheses of two true gallotannins, a hexagalloylglucopyranose and a decagalloylated compound whose structure is commonly used to depict "tannic acid", are now described. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid ß-peptide (Aß) aggregation inâ vitro, and monogalloylated α-glucogallin and a natural ß-hexagalloylglucose are shown to be the strongest inhibitors.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/química , Ácido Gálico/química , Taninos/química , Estructura Molecular , PolifenolesRESUMEN
Oligomeric and protofibrillar aggregates formed by the amyloid-ß peptide (Aß) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer Aß42 peptide is more prone to aggregation than the more prevalent Aß40 . Detailed structural studies of Aß oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Aß that forms stable protofibrils and here we use solid-state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of Aß protomers into hexameric barrel-like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C-terminal hydrophobic regions of Aß, and hairpin loops extend from the core. The model accounts for why Aß42 forms oligomers and protofibrils more easily than Aß40 .
Asunto(s)
Péptidos beta-Amiloides/química , Amiloide/química , Amiloide/síntesis química , Modelos Moleculares , Resonancia Magnética Nuclear BiomolecularRESUMEN
As persons with Down's syndrome (DS) age into the third decade and beyond, they develop Alzheimer's disease (AD)-like histopathological changes in brain and may manifest progressive worsening of adaptive functions. Increasingly, persons with DS have near-normal to normal life spans; thus, it has become a therapeutic imperative to preserve adaptive functions and ability to live as independently as possible in the least restrictive environment throughout adulthood. Data suggest that these histopathological changes and worsening adaptive functions result, at least in part, from the binding of the amyloidogenic Aß1-42 peptide to α7 nicotinic acetylcholine receptors (α7nAChRs) on the surface of neurons, which can lead to the internalization of the tightly-bound complex and cell lysis. Pharmacotherapeutic targeting of the α7nAChR may inhibit the creation of the Aß1-42-α7nAChR complex, which has been observed both intraneuronally and as a component of the amyloid plaque seen in AD. Additionally, selective α7nAChR agonists may improve memory and cognition independently of their potential ability to attenuate the cytotoxicity of Aß1-42 and retard the deposition of amyloid plaques in adults with DS. However, there are conflicting data supporting an antagonist strategy to improve cognition in the presence of elevated levels of Aß amyloidogenic peptides, as well as to prevent emergence of pyramidal neuron hyperexcitability. A major challenge to the implementation of clinical trials of targeted α7nAChR interventions in adults with DS will be the ability to detect medication-induced changes in cognition in the context of intellectual disability. The Review will consider some of the current evidence supporting both the role of the Aß1-42-α7nAChR complex in the pathogenesis of the AD-like histopathology in adult persons with DS, and pharmacotherapeutic interventions with α7nAChR agonists.
Asunto(s)
Cognición/efectos de los fármacos , Demencia/prevención & control , Síndrome de Down/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Cognición/fisiología , Demencia/fisiopatología , Síndrome de Down/fisiopatología , Humanos , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Fragmentos de Péptidos/metabolismoRESUMEN
Small oligomers of the amyloidâ ß (Aß) peptide, rather than the monomers or the fibrils, are suspected to initiate Alzheimer's disease (AD). However, their low concentration and transient nature under physiological conditions have made structural investigations difficult. A method for addressing such problems has been developed by combining rapid fluorescence techniques with slower two-dimensional solid-state NMR methods. The smallest Aß40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10-21 and 30-40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22-29) and the N-terminal tail (residues 1-9) are strikingly different. Notably, ten of eleven known Aßâ mutants that are linked to familial AD map to these two regions. Our results provide potential structural cues for AD therapeutics and also suggest a general method for determining transient protein structures.
Asunto(s)
Péptidos beta-Amiloides/genética , Fragmentos de Péptidos/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Membrana Celular/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Mutación , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/toxicidad , Pliegue de Proteína , Estructura Terciaria de ProteínaRESUMEN
Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aß following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.