Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 91
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
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.

2.
Nano Lett ; 21(12): 5133-5142, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34097419

RESUMO

Fluorescence microscopy with optical sectioning capabilities is extensively utilized in biological research to obtain three-dimensional structural images of volumetric samples. Tunable lenses have been applied in microscopy for axial scanning to acquire multiplane images. However, images acquired by conventional tunable lenses suffer from spherical aberration and distortions. Here, we design, fabricate, and implement a dielectric Moiré metalens for fluorescence imaging. The Moiré metalens consists of two complementary phase metasurfaces, with variable focal length, ranging from ∼10 to ∼125 mm at 532 nm by tuning mutual angles. In addition, a telecentric configuration using the Moiré metalens is designed for high-contrast multiplane fluorescence imaging. The performance of our system is evaluated by optically sectioned images obtained from HiLo illumination of fluorescently labeled beads, as well as ex vivo mice intestine tissue samples. The compact design of the varifocal metalens may find important applications in fluorescence microscopy and endoscopy for clinical purposes.


Assuntos
Lentes , Animais , Endoscopia , Iluminação , Camundongos , Microscopia de Fluorescência
3.
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
4.
IEEE Trans Med Imaging ; 40(11): 3229-3237, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34152982

RESUMO

Quantitative differential phase-contrast (qDPC) imaging is a label-free phase retrieval method for weak phase objects using asymmetric illumination. However, qDPC imaging with fewer intensity measurements leads to anisotropic phase distribution in reconstructed images. In order to obtain isotropic phase transfer function, multiple measurements are required; thus, it is a time-consuming process. Here, we propose the feasibility of using deep learning (DL) method for isotropic qDPC microscopy from the least number of measurements. We utilize a commonly used convolutional neural network namely U-net architecture, trained to generate 12-axis isotropic reconstructed cell images (i.e. output) from 1-axis anisotropic cell images (i.e. input). To further extend the number of images for training, the U-net model is trained with a patch-wise approach. In this work, seven different types of living cell images were used for training, validation, and testing datasets. The results obtained from testing datasets show that our proposed DL-based method generates 1-axis qDPC images of similar accuracy to 12-axis measurements. The quantitative phase value in the region of interest is recovered from 66% up to 97%, compared to ground-truth values, providing solid evidence for improved phase uniformity, as well as retrieved missing spatial frequencies in 1-axis reconstructed images. In addition, results from our model are compared with paired and unpaired CycleGANs. Higher PSNR and SSIM values show the advantage of using the U-net model for isotropic qDPC microscopy. The proposed DL-based method may help in performing high-resolution quantitative studies for cell biology.


Assuntos
Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Microscopia de Contraste de Fase
5.
Drug Deliv Transl Res ; 11(4): 1498-1508, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34024014

RESUMO

Transdermal drug delivery systems (TDDS) have many advantages and represent an excellent alternative to oral delivery and hypodermic injections. TDDS are more convenient and less invasive tools for disease and viral infection treatment, prevention, detection, and surveillance. The emerging development of microneedles for TDDS has facilitated improved skin barrier penetration for the delivery of macromolecules or hydrophilic drugs. Microneedle TDDS patches can be fabricated to deliver virus vaccines and potentially provide a viable alternative vaccine modality that offers improved immunogenicity, thermostability, simplicity, safety, and compliance as well as sharp-waste reduction, increased cost-effectiveness, and the capacity for self-administration, which could improve vaccine distribution. These advantages make TDDS-based vaccine delivery an especially well-suited option for treatment of widespread viral infectious diseases including pandemics. Because microneedle-based bioassays employ transdermal extraction of interstitial fluid or blood, they can be used as a minimally invasive approach for surveying disease markers and providing point-of-care (POC) diagnostics. For cutaneous viral infections, TDDS can provide localized treatment with high specificity and less systemic toxicity. In summary, TDDS, especially those that employ microneedles, possess special attributes that can be leveraged to reduce morbidity and mortality from viral infectious diseases. In this regard, they may have considerable positive impact as a modality for improving global health. In this article, we introduce the possible role and summarize the current literature regarding TDDS applications for fighting common cutaneous or systemic viral infectious diseases, including herpes simplex, varicella or herpes zoster, warts, influenza, measles, and COVID-19.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Microinjeções/métodos , Administração Cutânea , Animais , Antivirais/imunologia , Antivirais/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Humanos , Microinjeções/tendências
6.
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
7.
Polymers (Basel) ; 13(4)2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33670014

RESUMO

Intravitreal injections are clinically established procedures in the treatment of posterior eye diseases, such as wet age-related macular degeneration (wet AMD) which requires monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) protein drugs that can lead to complications due to frequent dosing. In this study, we designed a composite drug delivery system (DDS) consisting of drug-loaded poly (lactide-co-glycolide) (PLGA) nanoparticles and a chemically crosslinked hyaluronan hydrogel to reduce the dosing frequency. The morphology, size, composition, and drug loading efficiency of the prepared nanoparticles were characterized. The properties of the modified hyaluronan polymers used were also examined. The degree of swelling/degradation and controlled release ability of the hyaluronan hydrogel and the composite DDS were identified using bovine serum albumin (BSA) as a model drug. The results show that this system can retain 75% of its wet weight without losing its integrity and release the model drug at the rate of 0.4 µg/day for more than two months under physiological conditions. In addition, the nanoparticulate formulation of the system can further improve bioavailability of the drugs by penetrating deep into the retinal layers. In conclusion, the proposed composite DDS is easily prepared with biocompatible materials and is promising for providing the sustained release of the protein drugs as a better treatment for ocular neovascular diseases like wet AMD.

9.
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
10.
Opt Express ; 28(25): 37177-37187, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33379556

RESUMO

Optical sectioning fluorescence microscopy provides high contrast images of volumetric samples and has been widely used for many biological applications. However, simultaneously acquiring multi-color fluorescence images require additional optical elements and devices, which are bulky, wavelength specific, and not cost-effective. In this paper, wavelength-coded volume holographic gratings (WC-VHGs) based optical sectioning fluorescence microscopy is proposed to simultaneously offer multi-color fluorescence images with fine out-of-focus background rejection. Due to wavelength degeneracy, multiplexed WC-VHGs are capable of acquiring multi-wavelength fluorescence images in a single shot, and displaying the laterally separated multi-wavelength images onto CCD. In our system optical sectioning capability is achieved through speckle illumination and HiLo imaging method. To demonstrate imaging characteristics of our system, dual-wavelength fluorescence images of both standard fluorescent microspheres and ex vivo mT/mG mice cardiac tissue are presented. Current results may find important applications in hyperspectral imaging for biomedical research.


Assuntos
Coração/diagnóstico por imagem , Holografia/métodos , Microscopia de Fluorescência/métodos , Animais , Fluorescência , Processamento de Imagem Assistida por Computador , Iluminação/instrumentação , Camundongos , Microesferas , Imagem Óptica/métodos , Fenômenos Ópticos
11.
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.

12.
J Biomed Opt ; 25(12)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33247561

RESUMO

SIGNIFICANCE: Differential phase contrast (DPC) is a well-known imaging technique for phase imaging. However, simultaneously acquiring multidepth DPC images is a non-trivial task. We propose simultaneous multiplane DPC imaging using volume holographic microscopy (VHM). AIM: To design and implement a new configuration of DPC-VHM for multiplane imaging. APPROACH: The angularly multiplexed volume holographic gratings (AMVHGs) and the wavelength-coded volume holographic gratings (WC-VHGs) are used for this purpose. To obtain asymmetric illumination for DPC images, a dynamic illumination system is designed by modifying the regular Köhler illumination using a thin film transistor panel (TFT-panel). RESULTS: Multidepth DPC images of standard resolution chart and biosamples were used to compare imaging performance with the corresponding bright-field images. An average contrast enhancement of around three times is observed for target resolution chart by DPC-VHM. Imaging performance of our system is studied by modulation transfer function analysis, which suggests that DPC-VHM not only suppresses the DC component but also enhances high-frequency information. CONCLUSIONS: Proposed DPC-VHM can acquire multidepth-resolved DPC images without axial scanning. The illumination part of the system is adjustable so that the system can be adapted to bright-field mode, phase contrast mode, and DPC mode by controlling the pattern on the TFT-panel.


Assuntos
Holografia , Microscopia , Testes Diagnósticos de Rotina , Iluminação , Microscopia de Contraste de Fase
13.
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
14.
Biomed Microdevices ; 22(4): 63, 2020 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889555

RESUMO

Cell therapy is used to treat various diseases and to repair injuries. Cell delivery is a crucial process that delivers cells to target sites. Cells must be precisely delivered to a target site and the cells that are delivered must be localized to the target site to repair damaged tissue. For stem cell therapy, the most convenient method of cell delivery involves directly injecting cells into damaged tissue. Other strategies use carriers to transplant stem cells into damaged tissue. These are termed, stem cell delivery systems (SCDSs). Micro-needle arrays are minimally invasive transdermal delivery systems. The devices can pass through the stratum corneum barrier and deliver macromolecules into the skin. They can also access the microcirculation system in the skin. This study fabricates PMMA micro-needle using a two-stage micro-molding method. Cells are seeded on the micro-needle arrays and then transferred into the target tissue. Collagen hydrogel is used as a model biomimetic tissue. Cells are efficiently delivered to regions of interest, collagen hydrogel, by using this system. The delivery rate is about 83.2%. This demonstrates that micro-needle arrays allow very efficient delivery of cells.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/instrumentação , Sistemas de Liberação de Medicamentos/instrumentação , Microinjeções/instrumentação , Agulhas , Animais , Humanos , Células-Tronco/citologia
15.
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
16.
Acta Pharm Sin B ; 10(7): 1205-1215, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32318327

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

17.
J Med Chem ; 63(6): 3370-3380, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32115956

RESUMO

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC50 = 1.31 µM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.


Assuntos
Demência Vascular/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Xantonas/uso terapêutico , Aminopiridinas/metabolismo , Animais , Benzamidas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/metabolismo , Cães , Desenho de Fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacocinética , Ligação Proteica , Rolipram/metabolismo , Rolipram/uso terapêutico , Relação Estrutura-Atividade , Vômito/prevenção & controle , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/farmacocinética
18.
ACS Chem Neurosci ; 11(7): 1058-1071, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105440

RESUMO

Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.


Assuntos
Ligação de Hidrogênio/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Diester Fosfórico Hidrolases/metabolismo , Descoberta de Drogas/métodos , Humanos , Modelos Moleculares , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade
19.
Mol Imaging Biol ; 22(2): 313-323, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31140111

RESUMO

PURPOSE: Sodium taurocholate cotransporting polypeptide (NTCP) is a transmembrane protein responsible for delivering indocyanine green (ICG), an ideal infrared fluorescent dye, from extracellular space into the cytoplasm. Additionally, NTCP located in the hepatocyte membrane is the portal for hepatitis B and D virus (HBV/HDV) infections. This study verified the feasibility of NTCP as a reporter and further established a drug-screening platform for HBV/HDV infections. PROCEDURES: NTCP was transduced into HT-29, a colorectal cancer cell line. To examine the use of NTCP as a reporter, NTCP-expressing cells were treated with ICG and examined through flow cytometry, an in vivo imaging system (IVIS), and confocal microscopy. Furthermore, ICG was administrated to NTCP-expressing tumor-bearing nude mice and examined using the IVIS. To study the drug-screening platform, NTCP-expressing cells were treated with cyclosporin A, an NTCP inhibitor, and ICG, and examined using a multimode detection platform. Moreover, nude mice were injected with NTCP inhibitors and ICG, and subsequently, their ICG signal was examined in vivo and in the blood. RESULTS: In the reporter study, the ICG signal was higher in NTCP-expressing cells/tumors than in control cells/tumors after ICG treatment. In the drug-screening platform study, NTCP-expressing cells had decreased ICG intensity after treatment with NTCP inhibitors and ICG. Nude mice that were administered cyclosporin A had lower ICG intensity in the liver and higher intensity in the peripheral tissue and blood. CONCLUSIONS: NTCP and ICG form an ideal reporter system with extensive applications in cancer biology, robust drug-drug interactions, and drug screening in HBV/HDV infections.


Assuntos
Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Hepatite D/diagnóstico , Hepatite D/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/genética , Ácido Taurocólico/química , Animais , Linhagem Celular Tumoral , Ciclosporina/metabolismo , Citoplasma/metabolismo , Feminino , Corantes Fluorescentes , Genes Reporter , Células HEK293 , Vírus da Hepatite B , Vírus Delta da Hepatite , Hepatócitos/metabolismo , Humanos , Verde de Indocianina , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
20.
Pharmaceutics ; 11(11)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717826

RESUMO

In recent decades, the decellularized extracellular matrix (ECM) has shown potential as a promising scaffold for tissue regeneration. In this study, an organic acid decellularized lymph node (dLN) was developed as a carrier for dendritic cells (DCs) to induce antitumor immunity. The dLNs were prepared by formic acid, acetic acid, or citric acid treatment. The results showed highly efficient removal of cell debris from the lymph node and great preservation of ECM architecture and biomolecules. In addition, bone marrow dendritic cells (BMDCs) grown preferably inside the dLN displayed the maturation markers CD80, CD86, and major histocompatibility complex (MHC)-II, and they produced high levels of interleukin (IL)-1ß, IL-6, and IL-12 cytokines when stimulated with ovalbumin (OVA) and CpG oligodeoxynucleotides (CPG-ODN). In an animal model, the BMDC-dLN completely rejected the E.G7-OVA tumor. Furthermore, the splenocytes from BMDC-dLN-immunized mice produced more interferon gamma, IL-4, IL-6, and IL-2, and they had a higher proliferation rate than other groups when re-stimulated with OVA. Hence, BMDC-dLN could be a promising DC-based scaffold for in vivo delivery to induce potent antitumor immunity.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...