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1.
PLoS Pathog ; 18(1): e1010270, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35089988

RESUMO

ASFV is a large DNA virus that is highly pathogenic in domestic pigs. How this virus is sensed by the innate immune system as well as why it is so virulent remains enigmatic. In this study, we show that the ASFV genome contains AT-rich regions that are recognized by the DNA-directed RNA polymerase III (Pol-III), leading to viral RNA sensor RIG-I-mediated innate immune responses. We further show that ASFV protein I267L inhibits RNA Pol-III-RIG-I-mediated innate antiviral responses. I267L interacts with the E3 ubiquitin ligase Riplet, disrupts Riplet-RIG-I interaction and impairs Riplet-mediated K63-polyubiquitination and activation of RIG-I. I267L-deficient ASFV induces higher levels of interferon-ß, and displays compromised replication both in primary macrophages and pigs compared with wild-type ASFV. Furthermore, I267L-deficiency attenuates the virulence and pathogenesis of ASFV in pigs. These findings suggest that ASFV I267L is an important virulence factor by impairing innate immune responses mediated by the RNA Pol-III-RIG-I axis.


Assuntos
Vírus da Febre Suína Africana/patogenicidade , Imunidade Inata/imunologia , Fatores de Virulência/imunologia , Virulência/imunologia , Febre Suína Africana/imunologia , Vírus da Febre Suína Africana/imunologia , Animais , RNA Polimerase III/imunologia , Receptores de Superfície Celular/imunologia , Suínos
2.
J Med Chem ; 64(9): 5816-5837, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33929863

RESUMO

We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment.


Assuntos
Anticonvulsivantes/química , Carbamatos/química , Desenho de Fármacos , Animais , Anticonvulsivantes/uso terapêutico , Carbamatos/metabolismo , Carbamatos/uso terapêutico , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Eletrochoque , Meia-Vida , Humanos , Canais de Potássio KCNQ/química , Canais de Potássio KCNQ/metabolismo , Camundongos , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Fenilenodiaminas/uso terapêutico , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico , Convulsões/etiologia , Relação Estrutura-Atividade
3.
Cell Cycle ; 15(6): 850-60, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26901336

RESUMO

Foot-and-mouth disease is a highly contagious viral disease of cloven-hoofed animals that is caused by foot-and-mouth disease virus (FMDV). To replicate efficiently in vivo, FMDV has evolved methods to circumvent host antiviral defense mechanisms, including those induced by interferons (IFNs). Previous research has focused on the effect of FMDV L(pro) and 3C(pro) on type I IFNs. In this study, FMDV VP3 was found to inhibit type II IFN signaling pathways. The overexpression of FMDV VP3 inhibited the IFN-γ-triggered phosphorylation of STAT1 at Tyr701 and the subsequent expression of downstream genes. Mechanistically, FMDV VP3 interacted with JAK1/2 and inhibited the tyrosine phosphorylation, dimerization and nuclear accumulation of STAT1. FMDV VP3 also disrupted the assembly of the JAK1 complex and degraded JAK1 but not JAK2 via a lysosomal pathway. Taken together, the results reveal a novel mechanism used by which FMDV VP3 counteracts the type II IFN signaling pathways.


Assuntos
Proteínas do Capsídeo/metabolismo , Interferon gama/metabolismo , Janus Quinase 1/metabolismo , Lisossomos/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Animais , Proteínas do Capsídeo/genética , Cricetulus , Regulação da Expressão Gênica , Genes Reporter , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/genética , Janus Quinase 1/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Luciferases/genética , Luciferases/metabolismo , Fosforilação , Ligação Proteica , Multimerização Proteica , Proteólise , Fator de Transcrição STAT1/genética , Tirosina/metabolismo
4.
Acta Pharmacol Sin ; 35(11): 1463-72, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25283506

RESUMO

AIM: TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1 (GLP-1) secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betulinic acid. METHODS: A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. RESULTS: Biological data revealed that the 3-α-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-ß-OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-α betulinic derivatives and enhanced the activity differences between 3-α and 3-ß derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. CONCLUSION: This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.


Assuntos
Receptores Acoplados a Proteínas G/agonistas , Triterpenos/farmacologia , Administração Oral , Animais , AMP Cíclico/metabolismo , Genes Reporter , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Estrutura Molecular , Triterpenos Pentacíclicos , Ratos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-Atividade , Transfecção , Triterpenos/administração & dosagem , Triterpenos/síntese química , Triterpenos/farmacocinética , Ácido Betulínico
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