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1.
Talanta ; 237: 122898, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34736714

RESUMO

A nucleolus as a prominent sub-nuclear, membraneless organelle plays a crucial role in ribosome biogenesis, which is in the major metabolic demand in a proliferating cell, especially in aggressive malignancies. We develop a γ-glutamyltranspeptidase (GGT)-activatable indole-quinolinium (QI) based cyanine consisting of a novel tripeptide fragment (Pro-Gly-Glu), namely QI-PG-Glu as a turn-on red fluorescent probe for the rapid detection of GGT-overexpressed A549 cancer cells in vivo. QI-PG-Glu can be triggered by GGT to rapidly release an activated fluorophore, namely HQI, in two steps including the cleavage of the γ-glutamyl group recognized by GGT and the rapid self-driven cyclization of the Pro-Gly linker. HQI exhibits dramatically red fluorescence upon binding to rRNA for imaging of nucleolus in live A549 cells. HQI also intervenes in rRNA biogenesis by declining the RNA Polymerase I transcription, thus resulting in cell apoptosis via a p53 dependent signaling pathway. Our findings may provide an alternative avenue to develop multifunctional cancer cell-specific nucleolus-targeting fluorescent probes with potential anti-cancer effects.


Assuntos
Neoplasias , Quinolinas , Fluorescência , Corantes Fluorescentes , Indóis , Neoplasias/diagnóstico por imagem , Quinolinas/farmacologia , gama-Glutamiltransferase
2.
Mediators Inflamm ; 2021: 9955168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602860

RESUMO

Severe community-acquired pneumonia (sCAP) early in life is a leading cause of morbidity, mortality, and irreversible sequelae. Herein, we report the clinical, etiological, and immunological characteristics of 62 children age < 1 year. We measured 27 cytokines in plasma and bronchoalveolar lavage (BAL) from 62 children age < 1 year who were diagnosed with CAP, and then, we analyzed correlations among disease severity, clinical parameters, and etiology. Of the entire cohort, three cytokines associated with interleukin-17- (IL-17-) producing helper T cells (Th17 cells), IL-1ß, IL-6, and IL-17, were significantly elevated in sCAP patients with high fold changes (FCs); in BAL, these cytokines were intercorrelated and associated with blood neutrophil counts, Hb levels, and mixed bacterial-viral infections. BAL IL-1ß (area under the curve (AUC) 0.820), BAL IL-17 (AUC 0.779), and plasma IL-6 (AUC 0.778) had remarkable predictive power for sCAP. Our findings revealed that increased local Th17 cell immunity played a critical role in the development of sCAP in children age < 1 year. Th17 cell-related cytokines could serve as local and systemic inflammatory indicators of sCAP in this age group.

4.
J Med Chem ; 64(18): 13736-13751, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34520193

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.

5.
J Control Release ; 337: 417-430, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324896

RESUMO

The majority (~80%) of patients with cancer do not derive clinical benefit from current immunotherapy, largely due to attenuation of immune responses imposed by robust immunosuppression at tumor sites. Here, a cell-based tumor antigen delivery strategy was developed to boost tumor-specific immunity. Notably, the platform constructing ferric oxide nanoparticle-trained macrophages loading tumor antigens (MFe-N) acquired an immunostimulatory program and functioned as the tumoritropic "cytokine-microfactories" to sustainably produce high levels of multiple therapeutic cytokines (GM-CSF, TNFα, and MIP-1α), which are important in activation of immune cells with antitumor potential. Indeed, MFe-N markedly enhanced recruitment of the professional antigen-presenting cells, dendritic cells (DCs), to the tumor sites of an established B16F10 mouse melanoma model. Subsequently, MFe-N effectively delivered tumor antigens to DCs by gap junction-mediated cell-to-cell transmission. And this trafficking was critical for DC maturation to augment antitumor T-cell responses. Simultaneously, the "cytokine-microfactories" elicited high production of the tumoricidal effectors, and in turn blunted the pro-angiogenic activity of tumor-associated macrophages, resulting in conversion of the tumor-supporting milieu to a tumoricidal function that favored infiltration of antitumor T-cells. The findings provided a novel "cytokine-microfactories" harnessing effective delivery of tumor antigens and production of therapeutic cytokines to robustly promote antigen presentation and reshape the tumor immune milieu for priming antitumor immunity. This can enhance existing T-cell mediated immunotherapeutic potency and extend the curative potential immunotherapy to a broader range of patients.


Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Animais , Apresentação do Antígeno , Citocinas , Células Dendríticas , Junções Comunicantes , Humanos , Imunoterapia , Camundongos
6.
J Med Chem ; 64(13): 9537-9549, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142552

RESUMO

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-ß-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Descoberta de Drogas , Fibrose/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Ductos Biliares/metabolismo , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade
7.
Bioorg Chem ; 114: 105104, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34186466

RESUMO

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC50 of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t1/2 of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.

8.
ACS Chem Biol ; 16(5): 857-863, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33955736

RESUMO

A challenge for sensors targeting specific enzymes of interest in their native environment for direct imaging is that they rationally exploit a highly selective fluorescent probe with a high binding affinity to provide real-time detection. Immunohistochemical staining, proteomic analysis, or recent enzymatic fluorescent probes are not optimal for tracking specific enzymes directly in living cells. Herein, we introduce the concept of designing a highly effective fluorescent probe (BVQ1814) targeting phosphodiesterase 10A with a highly potent affinity and a >1000-fold subfamily selectivity by gaining insights into the three-dimensional structural information of the active site of the catalytic pocket. BVQ1814 showed an outstanding binding affinity for PDE10A in vitro and specifically detected PDE10A in living cells, indicating that most PDE10A was probably distributed in the lysosomes. We validated the PDE10A distribution in stable mCherry-PDE10A-overexpressing HepG2 cells. This probe delineated the profile of PDE10A in tissue sections and exhibited a remarkable therapeutic effect as a PDE10A inhibitor for treating pulmonary arterial hypertension. This concept will open up a new avenue for designing a highly effective fluorescent probe for tracking receptor proteins by taking full advantage of the structural information in the ligand-binding pocket of the target of interest.


Assuntos
Corantes Fluorescentes/química , Lisossomos/química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Catálise , Domínio Catalítico , Células HeLa , Células Hep G2 , Humanos , Lisossomos/ultraestrutura , Imagem Óptica , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/ultraestrutura , Ligação Proteica , Conformação Proteica , Proteômica
9.
J Med Chem ; 64(11): 7083-7109, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34042442

RESUMO

Cyclic nucleotide phosphodiesterases (PDEs) control the intracellular concentrations of cAMP and cGMP in virtually all mammalian cells. Accordingly, the PDE family regulates a myriad of physiological functions, including cell proliferation, differentiation and apoptosis, gene expression, central nervous system function, and muscle contraction. Along this line, dysfunction of PDEs has been implicated in neurodegenerative disorders, coronary artery diseases, chronic obstructive pulmonary disease, and cancer development. To date, 11 PDE families have been identified; however, their distinct roles in the various pathologies are largely unexplored and subject to contemporary research efforts. Indeed, there is growing interest for the development of isoform-selective PDE inhibitors as potential therapeutic agents. Similarly, the evolving knowledge on the various PDE isoforms has channeled the identification of new PET probes, allowing isoform-selective imaging. This review highlights recent advances in PDE-targeted PET tracer development, thereby focusing on efforts to assess disease-related PDE pathophysiology and to support isoform-selective drug discovery.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Descoberta de Drogas , Inibidores de Fosfodiesterase/química , Tomografia por Emissão de Pósitrons , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/uso terapêutico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Bioorg Med Chem Lett ; 41: 128016, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838306

RESUMO

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer's disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure-activity relationship (SAR) of lead compounds.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Descoberta de Drogas , Inibidores de Fosfodiesterase/farmacologia , Doença de Alzheimer/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2 , Relação Dose-Resposta a Droga , Fluoresceínas/análise , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
12.
Med Res Rev ; 41(3): 1775-1797, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33393116

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global crisis. As of November 9, COVID-19 has already spread to more than 190 countries with 50,000,000 infections and 1,250,000 deaths. Effective therapeutics and drugs are in high demand. The structure of SARS-CoV-2 is highly conserved with those of SARS-CoV and Middle East respiratory syndrome-CoV. Enzymes, including RdRp, Mpro /3CLpro , and PLpro , which play important roles in viral transcription and replication, have been regarded as key targets for therapies against coronaviruses, including SARS-CoV-2. The identification of readily available drugs for repositioning in COVID-19 therapy is a relatively rapid approach for clinical treatment, and a series of approved or candidate drugs have been proven to be efficient against COVID-19 in preclinical or clinical studies. This review summarizes recent progress in the development of drugs against SARS-CoV-2 and the targets involved.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , SARS-CoV-2/isolamento & purificação
13.
J Med Chem ; 63(24): 15852-15863, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33291877

RESUMO

To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 µM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Adenina/análogos & derivados , Desenho de Fármacos , Inibidores de Fosfodiesterase/química , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Adenina/química , Adenina/metabolismo , Adenina/farmacologia , Adenina/uso terapêutico , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , Demência Vascular/tratamento farmacológico , Demência Vascular/patologia , Modelos Animais de Doenças , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
Acta Pharm Sin B ; 10(12): 2339-2347, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33354505

RESUMO

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor A. As a result, a potent and highly selective PDE10A inhibitor, 14·3HCl (half maximal inhibitory concentration, IC50 = 2.8 nmol/L and >3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 14·3HCl [2.5 mg/kg, oral administration (p.o.)] was comparable to tadalafil (5.0 mg/kg, p.o.), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A-14 complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors.

15.
ACS Catal ; 10(3): 2198-2210, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33344000

RESUMO

Pyridoxal-5'-phosphate (PLP), the active form of vitamin B6, is an important and versatile coenzyme involved in a variety of enzymatic reactions, accounting for about 4% of all classified activities. However, the detailed catalytic reaction pathways for PLP-dependent enzymes remain to be explored. Methionine-γ-lyase (MGL), a promising alternative anti-tumor agent to conventional chemotherapies whose catalytic mechanism is highly desired for guiding further development of re-engineered enzymes, was used as a representative PLP-dependent enzyme, and the catalytic mechanism for L-Met elimination by MGL was explored at the first-principles quantum mechanical/molecular mechanical (QM/MM) level with umbrella sampling. The QM/MM calculations revealed that the enzymatic reaction pathway consists of 4 stages for a total of 19 reaction steps with five intermediates captured in available crystal structures. Furthermore, the more comprehensive role of PLP was revealed. Besides the commonly known role of "electron sink", coenzyme PLP can also assist proton transfer and temporarily store the excess proton generated in some intermediate states by using its hydroxyl group and phosphate group. Thus, PLP is participated in most of the 19 steps. This study not only provided a theoretical basis for further development and re-engineering MGL as a potential anti-tumor agent, but also revealed the comprehensive role of PLP which could be used to explore the mechanisms of other PLP-dependent enzymes.

16.
Proc Natl Acad Sci U S A ; 117(44): 27381-27387, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33051297

RESUMO

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , COVID-19 , Cloroquina/farmacologia , Proteases 3C de Coronavírus , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases , Dipiridamol/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , SARS-CoV-2
17.
Pharmacol Res ; 161: 105134, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798648

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Articulações/efeitos dos fármacos , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Antirreumáticos/efeitos adversos , Artrite Reumatoide/enzimologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Humanos , Articulações/enzimologia , Articulações/imunologia , Articulações/patologia , Inibidores de Fosfodiesterase/efeitos adversos , Sistemas do Segundo Mensageiro , Resultado do Tratamento
18.
J Med Chem ; 63(17): 9828-9837, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32794708

RESUMO

Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , Quinazolinas/metabolismo , Sítio Alostérico , Sequência de Aminoácidos , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Descoberta de Drogas , Masculino , Camundongos , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 5/química , Inibidores da Fosfodiesterase 5/farmacocinética , Ligação Proteica , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos Sprague-Dawley , Alinhamento de Sequência , Relação Estrutura-Atividade
20.
ACS Nano ; 14(9): 11341-11351, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32857496

RESUMO

Deposition and aggregation of ß-amyloid (Aß) peptides are demonstrated to be closely related to the pathogenesis of Alzheimer's disease (AD). Development of functional molecules capable of visualizing Aß1-40 aggregates with nanoscale resolution and even modulating Aß assembly has attracted great attention recently. In this work, we use monocyanine fluorophore as the lead structure to develop a set of deep red carbazole-based cyanine molecules, which can specifically bind with Aß1-40 fibril via electrostatic and van der Waals interactions. Spectroscopic and microscopic characterizations demonstrate that one of these fluorophores, (E)-1-(2-(2-methoxyethoxy)ethyl)-4-(2-(9-methyl-9H-carbazol-3-yl)vinyl) quinolinium iodide (me-slg) can bind to Aß1-40 aggregates with strong fluorescence enhancement. The photophysical properties of me-slg at the single-molecule level, including low "on/off" duty cycle, high photon output, and sufficient switching cycles, enable real-time nanoscopic imaging of Aß1-40 aggregates. Morphology-dependent toxic effect of Aß1-40 aggregates toward PC12 cells is unveiled from in situ nanoscopic fluorescence imaging. In addition, me-slg displays a strong inhibitory effect on Aß1-40 fibrillation in a low inhibitor-protein ratio (e.g., I:P = 0.2). A noticeably reduced cytotoxic effect of Aß1-40 after the addition of me-slg is also confirmed. These results afford promising applications in the design of a nanoscopic imaging probe for amyloid fibril as well as the development of inhibitors to modulate the fibrillation process.


Assuntos
Doença de Alzheimer , Piscadela , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Amiloide , Peptídeos beta-Amiloides , Animais , Corantes Fluorescentes , Células PC12 , Fragmentos de Peptídeos , Ratos
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