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1.
Nat Commun ; 13(1): 7133, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414666

RESUMO

The rational design of PROTACs is difficult due to their obscure structure-activity relationship. This study introduces a deep neural network model - DeepPROTACs to help design potent PROTACs molecules. It can predict the degradation capacity of a proposed PROTAC molecule based on structures of given target protein and E3 ligase. The experimental dataset is mainly collected from PROTAC-DB and appropriately labeled according to the DC50 and Dmax values. In the model of DeepPROTACs, the ligands as well as the ligand binding pockets are generated and represented with graphs and fed into Graph Convolutional Networks for feature extraction. While SMILES representations of linkers are fed into a Bidirectional Long Short-Term Memory layer to generate the features. Experiments show that DeepPROTACs model achieves 77.95% average prediction accuracy and 0.8470 area under receiver operating characteristic curve on the test set. DeepPROTACs is available online at a web server ( https://bailab.siais.shanghaitech.edu.cn/services/deepprotacs/ ) and at github ( https://github.com/fenglei104/DeepPROTACs ).


Assuntos
Aprendizado Profundo , Redes Neurais de Computação , Proteínas , Ubiquitina-Proteína Ligases/metabolismo
2.
Acta Pharmacol Sin ; 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36207403

RESUMO

Neuroblastoma is the most common and deadliest tumor in infancy. WDR5 (WD Repeat Domain 5), a critical factor supporting an N-myc transcriptional complex via its WBM site and interacting with chromosome via its WIN site, promotes the progression of neuroblastoma, thus making it a potential anti-neuroblastoma drug target. So far, a few WIN site inhibitors have been reported, and the WBM site disruptors are rare to see. In this study we conducted virtual screening to identify candidate hit compounds targeting the WBM site of WDR5. As a result, 60 compounds were selected as candidate WBM site inhibitors. Cell proliferation assay demonstrated 6 structurally distinct WBM site inhibitors, numbering as compounds 4, 7, 11, 13, 19 and 22, which potently suppressed 3 neuroblastoma cell lines (MYCN-amplified IMR32 and LAN5 cell lines, and MYCN-unamplified SK-N-AS cell line). Among them, compound 19 suppressed the proliferation of IMR32 and LAN5 cells with EC50 values of 12.34 and 14.89 µM, respectively, and exerted a moderate inhibition on SK-N-AS cells, without affecting HEK293T cells at 20 µM. Analysis of high-resolution crystal complex structure of compound 19 against WDR5 revealed that it competitively occupied the hydrophobic pocket where V264 was located, which might disrupt the interaction of MYC with WDR5 and further MYC-medicated gene transcription. By performing RNA-seq analysis we demonstrated the differences in molecular action mechanisms of the compound 19 and a WIN site inhibitor OICR-9429. Most interestingly, we established the particularly high synergy rate by combining WBM site inhibitor 19 and the WIN site inhibitor OICR-9429, providing a novel therapeutic avenue for neuroblastoma.

3.
Front Genet ; 13: 876308, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846155

RESUMO

In the context of global warming and continuous high temperatures in the northern part of China during summer, the mortality rate of our main breeding species, Strongylocentrotus intermedius, reached 80% in 2020. How sea urchins respond to high temperatures is of great concern to academia and industry. In this study, we examined the antioxidant enzyme activities of different color tube-footed sea urchins under heat stress and compared their transcriptome and microRNA (miRNA) profiles using RNA-Seq. The results showed that the antioxidant enzyme activities of sea urchins were altered by thermal stress, and the changes in peroxidase activities of red tube-footed sea urchins were particularly significant. Investigations revealed that 1,079 differentially expressed genes (DEGs), 11 DE miRNAs, and 104 "DE miRNA-DEG" pairs in total were detected in sea urchins under high temperature stress. Several mRNA and miRNAs were significantly changed (e.g. HSP70, DnaJ11, HYAL, CALR, miR-184-p5, miR-92a, miR-92c, and miR-124-p5), suggesting these genes and miRNAs exerted important functions in response to high temperature. At the transcriptional level, red tube-footed sea urchins were found to be more sensitive to high temperature and could respond to high temperature rapidly. DE miRNA-mRNA network showed that miR-92b-3p and PC-5p-7420 were the most corresponding miRNAs. Five mRNAs (DnaJ11, SAR1B, CALR, HYOU1, TUBA) may be potential markers of sea urchin response to high temperature. Possible interaction between miRNA-mRNA could be linked to protein folding in the endoplasmic reticulum, Phagosomes, and calcium transport. This study provides a theoretical basis for the molecular mechanism of sea urchin heat tolerance and information that will aid in the selection and breeding of sea urchins with high temperature tolerance.

4.
Poult Sci ; 101(8): 101962, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35690001

RESUMO

The aim of this study was to investigate the protective effect of trans-anethole (TA) on lipopolysaccharide-induced acute liver inflammation model of chickens by determining the levels of inflammatory mediators in serum and liver, relative mRNA expression and protein expression of inflammation-related genes in NF-κB signaling pathway. A total of 160 one-day-old male chickens (Arbor Acres) were assigned into 4 treatments with 8 replicates of 5 birds each. On d 20, the control group was intraperitoneally injected with sterile saline and the other groups were injected with lipopolysaccharide (LPS; 5 mg/kg body weight). There were no significant differences in average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR) among groups. However, compared with the control group, the LPS group significantly increased (P < 0.01) the serum levels of interleukin-6 (IL-6), interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and decreased (P < 0.01) the interleukin-10 (IL-10) level. TA attenuated (P < 0.01) these increases in IL-1ß, TNF-α, ALT, and AST levels and improved (P < 0.01) the IL-10 level. In liver, the groups fed with TA had lower (P < 0.01) concentrations of IL-6 and TNF-α as well as higher (P < 0.05) concentration of IL-10. Furthermore, TA downregulated (P < 0.05) the mRNA expression levels of nuclear factor kappa B p65 (NF-κB p65) and TNF-α, also upregulated (P < 0.05) IL-10 and inhibitor of NF-κB alpha (IκBα) upon LPS challenge. In protein level, supplementation of 600 mg/kg of TA downregulated (P < 0.05) and upregulated (P < 0.05) the protein expression of NF-κB p65 and IκBα, respectively. The present findings suggest that TA could alleviate the acute liver inflammation induced by LPS via blocking the activation of NF-κB and the 600 mg/kg of TA plays more fruitful role in protecting broilers against LPS stimulus.


Assuntos
Lipopolissacarídeos , NF-kappa B , Derivados de Alilbenzenos , Animais , Anisóis , Galinhas/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/veterinária , Interleucina-10/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/metabolismo , Masculino , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa
5.
J Nat Prod ; 85(2): 327-336, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35084181

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1-4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana. These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective Kd values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.


Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Floroglucinol/farmacologia , SARS-CoV-2/efeitos dos fármacos , Terpenos/farmacologia , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Cristalografia por Raios X , Sistemas de Liberação de Medicamentos , Dryopteris/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Simulação de Acoplamento Molecular , Estrutura Molecular , Realidade Virtual
6.
Acta Pharmacol Sin ; 43(2): 483-493, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33907306

RESUMO

The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.


Assuntos
Antivirais/farmacologia , Desenho de Fármacos , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
7.
Acta Pharmacol Sin ; 43(4): 788-796, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34349236

RESUMO

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , COVID-19/tratamento farmacológico , Humanos , Ligação Proteica , SARS-CoV-2
8.
J Med Chem ; 65(4): 2827-2835, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-34415156

RESUMO

The receptor recognition of the novel coronavirus SARS-CoV-2 relies on the "down-to-up" conformational change in the receptor-binding domain (RBD) of the spike (S) protein. Therefore, understanding the process of this change at the molecular level facilitates the design of therapeutic agents. With the help of coarse-grained molecular dynamic simulations, we provide evidence showing that the conformational dynamics of the S protein are globally cooperative. Importantly, an allosteric path was discovered that correlates the motion of the RBD with the motion of the junction between the subdomain 1 (SD1) and the subdomain 2 (SD2) of the S protein. Building on this finding, we designed non-RBD binding modulators to inhibit SARS-CoV-2 by prohibiting the conformational change of the S protein. Their inhibition effect and function stages at inhibiting SARS-CoV-2 were evaluated experimentally. In summary, our studies establish a molecular basis for future therapeutic agent design through allosteric effects.


Assuntos
Antivirais/farmacologia , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Células Cultivadas , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , SARS-CoV-2/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
9.
Artigo em Inglês | MEDLINE | ID: mdl-34942521

RESUMO

Strongylocentrotus intermedius is one of the most economically valuable sea urchin species in China, and its growth and survival are severely constrained by ocean warming and the hypoxia that often accompanies high water temperatures. To elucidate the molecular mechanisms of S. intermedius that regulate gene expression in response to multi-causal environmental stresses. We performed a de novo transcriptome analysis of coelomocyte from S. intermedius to heat (25 °C), hypoxia (2 mg/L), and the combined stress. We identified 35,635, 29,107, and 29,440 differentially expressed genes (DEGs) in S. intermedius cultured under high temperature, low oxygen, and combined stress, respectively. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses revealed that these DEGs mainly enriched the functional categories of "Protein processing in endoplasmic reticulum," and "Glutathione metabolism" by heat stress, such as HSP70, GSTO1, PDIA4. After hypoxic stress, "Notch signaling pathway" and metabolism-related pathways such as "Glycerolipid metabolism", "Pyruvate metabolism" were significantly enriched. Exposure to combined stress resulted in a two-factor additive effect at the transcriptome level and have a more extensive impact on the immune correlated pathways in S. intermedius than single stress, the expression of related immune genes (C3, C5, and AIFM2) were up-regulated. Quantitative real-time PCR (qRT-PCR) analysis of the expression of 18 DEGs confirmed the RNA-Seq results. Observations in the present study will improve the understanding of the molecular mechanism of S. intermedius in response to multi-causal environmental stress.


Assuntos
Strongylocentrotus , Animais , Perfilação da Expressão Gênica , Hipóxia/genética , Temperatura , Transcriptoma
10.
J Adv Res ; 33: 241-251, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34603793

RESUMO

Introduction: Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined. Objectives: In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model. Methods: Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin in vivo. Results: Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as π-π stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins. Conclusion: The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Lignanas , Animais , Furanos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Leucócitos Mononucleares , Lignanas/farmacologia , Lignanas/uso terapêutico , Camundongos
11.
Membranes (Basel) ; 11(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34564514

RESUMO

Ion concentration polarization (ICP) is a promising mechanism for concentrating and/or separating charged molecules. This work simulates the extraction of Li+ ions in a diluted high Mg2+/Li+ ratio salt lake brines based on free flow ICP focusing (FF-ICPF). The model solution of diluted brine continuously flows through the system with Li+ slightly concentrated and Mg2+ significantly removed by ICP driven by external pressure and perpendicular electric field. In a typical case, our results showed that this system could focus Li+ concentration by ~1.28 times while decreasing the Mg2+/Li+ ratio by about 85% (from 40 to 5.85). Although Li+ and Mg2+ ions are not separated as an end product, which is preferably required by the lithium industry, this method is capable of decreasing the Mg2+/Li+ ratio significantly and has great potential as a preprocessing technology for lithium extraction from salt lake brines.

12.
Front Chem ; 9: 659764, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368076

RESUMO

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still an emergent pandemic for humans. The virus infection is achieved by penetrating its spike protein to host cells via binding with ACE2. Moreover, recent studies show that SARS-CoV-2 may have multiple receptors that need to be further revealed. SARS-CoV-2 shares similar sequences of the spike protein with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which can invade host cells by binding to either DPP4 or sialic acids. Sialic acids can be linked to the terminal of glycoproteins and gangliosides are used as one of the receptors of many types of viruses. Therefore, it is very interesting to determine whether sialic acid is a potential receptor of SARS-CoV-2. To address this question, we took N-Acetylneuraminic acid (Neu5Ac), a type of predominant sialic acid found in human cells, as the molecular probe to computationally search the surface of the spike protein to locate the potential binding sites of Neu5Ac. SPR analysis and mass spectrum analysis confirmed the interaction between Neu5Ac and spike protein. This study shows that sialic acids can moderately interact with the spike protein of SARS-CoV-2 by binding between the two RBDs of the spike protein, indicating it could be a potential secondary or auxiliary receptor of SARS-CoV-2.

13.
Acta Pharmacol Sin ; 42(3): 482-490, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32581257

RESUMO

TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC50 values of TPN729 and M3 for PDE5A were 6.17 ± 0.48 and 7.94 ± 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , Pirimidinonas/metabolismo , Sulfonamidas/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/farmacocinética , Cães , Humanos , Macaca fascicularis , Masculino , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/farmacocinética , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Especificidade da Espécie , Sulfonamidas/sangue , Sulfonamidas/farmacocinética
14.
Eur J Med Chem ; 211: 113004, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33218684

RESUMO

Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Psoríase/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
15.
Biochem Pharmacol ; 177: 113958, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251674

RESUMO

Phosphodiesterase-4 (PDE4) functions as a critical intracellular enzyme in immune cells and keratinocytes through the hydrolysis of cAMP. Inhibition of PDE4 has been considered as an effective therapeutic strategy in multiple inflammatory diseases. This study was intended to assess the anti-inflammatory effects of the PDE4 inhibitor, DC591017, both in vitro and in vivo. Murine RAW264.7 cells, BMDMs, BMDCs, and human NHEKs were incubated with DC591017 and then inflammatory mediators, intracellular cAMP and cAMP-mediated signaling pathways were analyzed. Carrageenan-induced acute inflammation in murine air pouches and rat paws, as well as imiquimod (IMQ)-induced psoriasis-like skin lesions were conducted to explore the therapeutic effects and underlying mechanisms of DC591017. We demonstrated herein that DC591017 suppressed the inflammatory responses of macrophages and DCs through promoting cAMP-dependent PKA-CREB signaling. Addition of forskolin functioned synergistically with DC591017, which could be blocked following H89 intervention or knockdown of PKA expression by siRNA transfection. In vivo, DC591017 treatment alleviated the leukocytes infiltration and secretion of inflammatory cytokines in murine air pouches and significantly attenuated carrageenan-induced paw swelling in rats. Moreover, we also illustrated that topical application of DC591017 ointment ameliorated IMQ-caused experimental psoriatic skin lesions, as evidenced by decreasing epidermal thickening and inflammatory infiltrations to inflamed skins. Consistently, DC591017 decreased expression of PDE4 isoforms and subsequently regulated PKA-CREB and NF-κB signaling. In brief, our study brought out a patent PDE4 inhibitor with robust anti-inflammation and provided the credible evidence in the treatment of patients with psoriasis.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Feminino , Humanos , Imiquimode , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Fosfodiesterase 4/química , Psoríase/induzido quimicamente , Psoríase/metabolismo , Psoríase/prevenção & controle , Células RAW 264.7 , Ratos Sprague-Dawley
16.
J Med Chem ; 63(8): 4090-4106, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202425

RESUMO

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Descoberta de Drogas/métodos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Células 3T3 , Administração Oral , Animais , Anti-Inflamatórios/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/metabolismo , Resultado do Tratamento
17.
J Nat Prod ; 83(4): 1229-1237, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32100544

RESUMO

Thirty-two diterpenoids were obtained from the root bark of Pinus massoniana, and, among them, five compounds (pinmassins A-E) were identified as undescribed analogues. Spectroscopic methods, X-ray single-crystal diffraction analysis, and ECD calculations were applied to establish the structure of the new isolates. Pinmassin D (4) and abieta-8,11,13,15-tetraen-18-oic acid (23) showed moderate phosphodiesterase type 4D (PDE4D) inhibitory effects with IC50 values of 2.8 ± 0.18 and 3.3 ± 0.50 µM, respectively, and their binding modes were investigated by a molecular docking study.


Assuntos
Diterpenos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pinus/química , Casca de Planta/química , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Simulação de Acoplamento Molecular , Diester Fosfórico Hidrolases/química
18.
iScience ; 23(2): 100857, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32058968

RESUMO

Hsp90 is a target for anti-cancer drug development. Both the conformational events tuned by ATP/ADP and co-chaperones and the chaperoning cycle timing are required for Hsp90's fully functional display. Interfering with either one of the conformational events or the cycle timing will down-regulate Hsp90's function. In this manuscript, non-covalent allosteric modulators (SOMCL-16-171 and SOMCL-16-175) targeting Hsp90α's middle domain (Hsp90M) were developed for the first time. Multiple techniques were then applied to characterize the interactions between two active compounds and Hsp90α. Two loops and one α-helix (F349-N360, K443-E451, and D372-G387) in Hsp90M were identified responsible for the recognition of SOMCL-16-171 and SOMCL-16-175. Meanwhile, the binding of SOMCL-16-171 and SOMCL-16-175 to Hsp90M was demonstrated to allosterically modulate the structure and function of Hsp90α's N-terminal domain. Finally, cellular assays were conducted to evaluate the cellular activity of SOMCL-16-175, and the results indicate that SOMCL-16-175 destabilizes Hsp90's client proteins and reduces cell viability.

19.
J Med Chem ; 62(11): 5579-5593, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31099559

RESUMO

Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.


Assuntos
Desenho de Fármacos , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Células CACO-2 , Domínio Catalítico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacocinética , Tetra-Hidroisoquinolinas/uso terapêutico , Distribuição Tecidual
20.
J Med Chem ; 62(10): 4979-4990, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31021628

RESUMO

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Animais , Cães , Desenho de Fármacos , Feminino , Meia-Vida , Masculino , Inibidores da Fosfodiesterase 5/síntese química , Pirimidinas/síntese química , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Citrato de Sildenafila/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
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