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1.
Sci Rep ; 6: 33663, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27645381

RESUMO

Hand, Foot and Mouth Disease is a highly contagious disease caused by a range of human enteroviruses. Outbreaks occur regularly, especially in the Asia-Pacific region, putting a burden on public healthcare systems. Currently, there is no antiviral for treating this infectious disease and the only vaccines are limited to circulation in China, presenting an unmet medical need that needs to be filled urgently. The human enterovirus 3 C protease has been deemed a plausible drug target due to its essential roles in viral replication. In this study, we designed and synthesized 10 analogues of the Rhinovirus 3 C protease inhibitor, Rupintrivir, and tested their 3 C protease inhibitory activities followed by a cellular assay using human enterovirus 71 (EV71)-infected human RD cells. Our results revealed that a peptide-based compound containing a trifluoromethyl moiety to be the most potent analogue, with an EC50 of 65 nM, suggesting its potential as a lead for antiviral drug discovery.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Enterovirus Humano A/enzimologia , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteases Virais 3C , Antivirais/química , Linhagem Celular , Cisteína Endopeptidases , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Enterovirus/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Peptídeos/química , Inibidores de Proteases/química , Replicação Viral/efeitos dos fármacos
2.
J Biol Chem ; 291(34): 17743-53, 2016 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-27365392

RESUMO

Bacterial topoisomerases are attractive antibacterial drug targets because of their importance in bacterial growth and low homology with other human topoisomerases. Structure-based drug design has been a proven approach of efficiently developing new antibiotics against these targets. Past studies have focused on developing lead compounds against the ATP binding pockets of both DNA gyrase and topoisomerase IV. A detailed understanding of the interactions between ligand and target in a solution state will provide valuable information for further developing drugs against topoisomerase IV targets. Here we describe a detailed characterization of a known potent inhibitor containing a 9H-pyrimido[4,5-b]indole scaffold against the N-terminal domain of the topoisomerase IV E subunit from Escherichia coli (eParE). Using a series of biophysical and biochemical experiments, it has been demonstrated that this inhibitor forms a tight complex with eParE. NMR studies revealed the exact protein residues responsible for inhibitor binding. Through comparative studies of two inhibitors of markedly varied potencies, it is hypothesized that gaining molecular interactions with residues in the α4 and residues close to the loop of ß1-α2 and residues in the loop of ß3-ß4 might improve the inhibitor potency.


Assuntos
DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Escherichia coli/enzimologia , Inibidores da Topoisomerase/química , Humanos , Indóis/química , Ressonância Magnética Nuclear Biomolecular , Domínios Proteicos , Estrutura Secundária de Proteína
3.
J Enzyme Inhib Med Chem ; 31(2): 332-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25792507

RESUMO

Enterovirus 71 (EV71) is a highly infectious pathogen primarily responsible for Hand, Foot, and Mouth Disease, particularly among children. Currently, no approved antiviral drug has been developed against this disease. The EV71 3C protease is deemed an attractive drug target due to its crucial role in viral polyprotein processing. Rupintrivir, a peptide-based inhibitor originally developed to target the human rhinovirus 3C protease, was found to inhibit the EV71 3C protease. In this communication, we report the inhibitory activities of 30 Rupintrivir analogs against the EV71 3C protease. The most potent inhibitor, containing a P2 ring-constrained phenylalanine analog (compound 9), was found to be two-fold more potent than Rupintrivir (IC50 value 3.4 ± 0.4 versus 7.3 ± 0.8 µM). Our findings suggest that employing geometrically constrained residues in peptide-based protease inhibitors can potentially enhance their inhibitory activities.


Assuntos
Enterovirus Humano A/enzimologia , Peptidomiméticos/farmacologia , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Proteínas Virais/antagonistas & inibidores , Proteases Virais 3C , Antivirais/química , Antivirais/farmacologia , Técnicas de Química Sintética , Cristalografia por Raios X , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Concentração Inibidora 50 , Isoxazóis/química , Isoxazóis/farmacologia , Peptidomiméticos/síntese química , Peptidomiméticos/química , Fenilalanina/análogos & derivados , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Valina/análogos & derivados , Proteínas Virais/química , Proteínas Virais/metabolismo
4.
Biochem Biophys Res Commun ; 467(4): 961-6, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26471301

RESUMO

Bacterial topoisomerase IV (ParE) is essential for DNA replication and serves as an attractive target for antibacterial drug development. The X-ray structure of the N-terminal 24 kDa ParE, responsible for ATP binding has been solved. Due to the accessibility of structural information of ParE, many potent ParE inhibitors have been discovered. In this study, a pyridylurea lead molecule against ParE of Escherichia coli (eParE) was characterized with a series of biochemical and biophysical techniques. More importantly, solution NMR analysis of compound binding to eParE provides better understanding of the molecular interactions between the inhibitor and eParE.


Assuntos
Trifosfato de Adenosina/metabolismo , DNA Topoisomerase IV/metabolismo , DNA Topoisomerase IV/farmacologia , Escherichia coli/enzimologia , Trifosfato de Adenosina/antagonistas & inibidores , Sequência de Aminoácidos , Antibacterianos/farmacologia , Ligação Competitiva , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Desenho de Fármacos , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular
5.
Chempluschem ; 80(8): 1250-1254, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31973307

RESUMO

Bacterial resistance to antibiotics remains a serious threat to global health. The gyrase B enzyme is a well-validated target for developing antibacterial drugs. Despite being an attractive target for antibiotic development, there are currently no gyrase B inhibitory drugs on the market. A fragment screen using 1,800 compounds identified 14 fragments that bind to Escherichia coli (E. coli) gyrase B. The detailed characterization of binding is described for all 14 fragments. With the aid of X-ray crystallography, modifications on a low-affinity fragment (KD =253 µM, IC50 =634 µM) has led to the development of a new class of potent phenyl aminopyrazole inhibitors against E. coli gyrase B (IC50 =160 nM). The study presented here combines the use of a set of biophysical techniques including differential scanning fluorimetry, nuclear magnetic resonance, isothermal titration calorimetry, and X-ray crystallography to methodically identify, quantify, and optimize fragments into new chemical leads.

6.
Peptides ; 52: 49-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24333681

RESUMO

The Murray Valley encephalitis virus (MVEV) and the West Nile virus (WNV) are mosquito-borne single-stranded RNA Flaviviruses responsible for many cases of viral encephalitis and deaths worldwide. The former is endemic in north Australia and Papua New Guinea while the latter has spread to different parts of the world and was responsible for a recent North American outbreak in 2012, resulting in 243 fatalities. There is currently no approved vaccines or drugs against MVEV and WNV viral infections. A plausible drug target is the viral non-structural NS2B/NS3 protease due to its role in viral replication. This trypsin-like serine protease recognizes and cleaves viral polyproteins at the C-terminal end of an arginine residue, opening an avenue for the development of peptide-based antivirals. This communication compares the P2 and P3 residue preferences of the MVEV and WNV NS2B/NS3 proteases using a series of C-terminal agmatine dipeptides. Our results revealed that both viral enzymes were highly specific toward lysines at the P2 and P3 positions, suggesting that a peptidomimetic viral protease inhibitor developed against one virus should also be active against the other.


Assuntos
Agmatina/química , Dipeptídeos/química , Vírus da Encefalite do Vale de Murray/enzimologia , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Proteínas não Estruturais Virais , Vírus do Nilo Ocidental/enzimologia , RNA Helicases/antagonistas & inibidores , RNA Helicases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
7.
Eur J Med Chem ; 68: 72-80, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23974013

RESUMO

Murray Valley encephalitis is an infectious disease spread by a mosquito-borne virus endemic in Papua New Guinea and northern Australia. In the past decade, it has spread to various regions of Australia and there is currently no therapeutic treatment against this disease. An attractive drug target is the viral serine protease NS2B/NS3, a critical enzyme involved in viral replication. Herein, we report the inhibitory activities of 37 C-terminal agmatine peptidomimetic inhibitors which led to the design of a novel structurally-constrained competitive inhibitor 38 possessing a Ki of 2.5±0.5 µM. We believe our data provides crucial insights into the viral protease active site specificity which could be used to facilitate drug design against Murray Valley encephalitis viral infections.


Assuntos
Vírus da Encefalite do Vale de Murray/enzimologia , Peptidomiméticos/farmacologia , Serina Proteases/metabolismo , Inibidores de Serina Proteinase/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Peptidomiméticos/síntese química , Peptidomiméticos/química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Especificidade por Substrato
8.
J Med Chem ; 56(11): 4497-508, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23672613

RESUMO

Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.


Assuntos
Quinolinas/síntese química , Tanquirases/antagonistas & inibidores , Cristalografia por Raios X , Bases de Dados Factuais , Estabilidade de Medicamentos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Solubilidade , Relação Estrutura-Atividade , Tanquirases/química , Termodinâmica
9.
Mol Cancer Ther ; 12(7): 1180-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23619303

RESUMO

Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, ß-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased ß-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule-mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Glioblastoma/patologia , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos , Camundongos Nus , Prognóstico , Transdução de Sinais , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto , Xenopus
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