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1.
Sheng Wu Gong Cheng Xue Bao ; 36(10): 2139-2150, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33169578

RESUMO

Thioredoxin reductase (TrxR) is one class of the most important antioxidant selenoproteins and is involved in regulating tumor genesis and progression. It has been reported that naphthoquinones can target and inhibit TrxR1 activity therefore produce reactive oxygen species (ROS) mediated by TrxR1, resulting into cellular redox imbalance and making the naphthoquinone compounds to become potential antitumor chemotherapy drugs. The purpose of this work is to explore the interaction between TrxR1 and menadione using biochemical and mass-spectrometric (MS) analyses, to further reveal the detailed mechanisms of TrxR1-mediated naphthoquinone reduction and inhibition of TrxR1 by naphthoquinone compounds. Using the site-directed mutagenesis and recombinantly expressed TrxR1 variants, we measured the steady-state kinetic parameters of menadione reduction mediated by TrxR1 and its variants, performed the inhibition analysis of menadione on TrxR1 activity, and eventually identified the interaction between menadione and TrxR1 through MS analysis. We found that Sec-to-Cys mutation at residue of 498 significantly enhanced the efficiency of TrxR1-mediated menadione reduction, though the Sec498 is capable to catalyze the menadione reduction, indicating that TrxR1-mediated menadione reduction is dominantly in a Se-independent manner. Mutation experiments showed that Cys498 is mainly responsible for menadione catalysis in comparison to Cys497, while the N-terminal Cys64 is slightly stronger than Cys59 regarding the menadione reduction. LC-MS results detected that TrxR1 was arylated with one molecule of menadione, suggesting that menadione irreversibly modified the hyper-reactive Sec residue at the C-terminus of selenoprotein TrxR1. This study revealed that TrxR1 catalyzes the reduction of menadione in a Se-independent manner meanwhile its activity is irreversibly inhibited by menadione. Hereby it will be useful for the research and development of naphthoquinone anticancer drugs targeting TrxR1.


Assuntos
Tiorredoxina Redutase 1 , Vitamina K 3 , Catálise , Desenvolvimento de Medicamentos , Oxirredução , Tiorredoxina Redutase 1/metabolismo , Vitamina K 3/química , Vitamina K 3/metabolismo
2.
Int J Med Sci ; 17(18): 3125-3145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173434

RESUMO

The use of multipronged measures, including traditional Chinese medicine (TCM), has greatly increased in response to the COVID-19 pandemic, and we found the use of TCM and is positively correlated with the regional cure rate in China (R=0.77, P<10-5). We analyzed 185 commonly administered TCM recipes comprised of 210 herbs nationwide to reveal mechanistic insight. Eight out of the 10 most commonly used herbs showed anti-coronavirus potential by intersecting with COVID-19 targets. Intriguingly, 17 compounds from the 5 most commonly used herbs were revealed to have direct anti-SARS-CoV-2 potential by docking with the two core structures [CoV spike (S) glycoprotein (6SVB) and CoV 3CL hydrolase (6LU7)]. Seven reported COVID-19 drugs served as positive controls; among them, retionavir (-7.828 kcal/mol) and remdesivir (-8.738 kcal/mol) performed best with 6VSB and 6LU7, respectively. The top candidate was madreselvin B (6SVB: -8.588 kcal/mol and 6LU7: -9.017 kcal/mol), an appreciable component of Flos Lonicerae. Eighty-six compounds from 22 unlisted herbs were further identified among 2,042 natural compounds, completing our arsenal for TCM formulations. The mechanisms have been implicated as multifactorial, including activation of immunoregulation (Th2, PPAR and IL10), suppression of acute inflammatory responses (IL-6, IL-1α/ß, TNF, COX2/1, etc.), enhancement of antioxidative activity (CAT and SOD1), and modulation of apoptosis (inhibited CASP3). It is of interest to understand the biological mechanisms of TCM recipes. We then analyzed 18 representative remedies based on molecular targets associated with 14 medical conditions over the disease course, e.g., pyrexia, coughing, asthenia, lymphopenia, cytokine storm, etc. The significant level of coherence (SLC) revealed, in part, the potential uses and properties of corresponding TCMs. Thus, herbal plants coordinate to combat COVID-19 in multiple dimensions, casting a light of hope before effective vaccines are developed.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Fitoterapia/métodos , Pneumonia Viral/tratamento farmacológico , Algoritmos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Desenvolvimento de Medicamentos , Medicamentos de Ervas Chinesas/classificação , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Pandemias , Fitoterapia/classificação , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
3.
Curr Top Med Chem ; 20(24): 2119-2125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33153418

RESUMO

Multidrug resistance in microbes poses a major health crisis and demands for the discovery of novel antimicrobial agents. The recent pandemic of SARS-CoV-2 has raised a public health emergency in almost all the countries of the world. Unlike viruses, a bacterium plays a significant role in various environmental issues such as bioremediation. Furthermore, biosurfactants produced by various bacterial species have an edge over traditionally produced chemical surfactants for its biodegradability, low toxicity and better interfacial activity with various applications in agriculture and industry. This special issue focuses on the global perspective of drug discovery for various antimicrobial, antiviral, and antifungal agents for infectious diseases. The issue also emphasizes the ongoing developments and the role of microbes in environmental remediation. We wish the articles published in this issue will enhance the current understanding in microbiology among the readers, and serve as the "seed of an idea" for drug development for ongoing COVID-19 pandemic.


Assuntos
Anti-Infecciosos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antivirais/uso terapêutico , Desenvolvimento de Medicamentos , Humanos , Pandemias
4.
Yakugaku Zasshi ; 140(11): 1329-1334, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132268

RESUMO

Biliary lipids primarily consist of bile salts, phospholipids, and cholesterol. Bile salts have potent detergent properties and deleterious effects on the cell membrane and are cytotoxic to hepatocytes. We have previously reported that phosphatidylcholine (PC), the predominant bile phospholipid, protects hepatocytes from the cytotoxicity of bile salts, whereas cholesterol reverses the cytoprotective effects of PC against bile salts. ABCB4, a member of the ATP-binding cassette transporter family, secretes biliary phospholipids, especially PC, from the hepatocytes into the bile. Using Abcb4 knockout mice and HEK293 cells that stably expressed ABCB4, we examined the effects of taurine- or glycine-conjugated cholate, ursodeoxycholate, and hyodeoxycholate on the ABCB4-mediated efflux of PC. We observed that the biliary secretion of PC in wild-type mice significantly increased following infusion of all the tested bile salts, especially taurohyodeoxycholate. On the other hand, the biliary secretion of PC in Abcb4 knockout mice was not affected by the bile salt infusions. The results also demonstrated that the efflux of PC from ABCB4-expressing HEK293 cells was significantly stimulated by taurohyodeoxycholate, which has a strong potential to form mixed micelles with PC. Furthermore, the results of our study emphasized the possibility that the specific interactions of bile salts with ABCB4 are necessary for the release of PC molecules from the binding pocket of ABCB4 into the aqueous environment. Further understanding of this mechanism will aid in the development of novel therapeutic agents for cholestatic liver diseases.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Ácidos e Sais Biliares/efeitos adversos , Bile/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/genética , Desenvolvimento de Medicamentos , Fosfatidilcolinas/farmacologia , Fosfolipídeos/metabolismo , Ácido Taurodesoxicólico/análogos & derivados , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Colesterol/farmacologia , Células HEK293 , Hepatócitos/metabolismo , Humanos , Camundongos Knockout , Fosfatidilcolinas/metabolismo , Ácido Taurodesoxicólico/farmacologia
5.
Emerg Microbes Infect ; 9(1): 2379-2380, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33059515

RESUMO

This commentary provides an overview and links to presentations of a recent virtual congress series organized by the International Society for Vaccines (ISV) focused on COVID-19 vaccines. The series provided the academic community and vaccine developers as well as the wider general public with balanced information of the global response and resources for COVID-19 vaccines under development featuring: 1) NGOs and the regulatory perspective, 2) the status of vaccine development efforts, and 3) panel discussions to present and discuss challenges. ISV is a non-profit scientific organization whose members work on all areas relevant to vaccines. ISV plans to host additional virtual symposia including regional meetings and incorporating other topics along with COVID-19 vaccines.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Desenvolvimento de Medicamentos/tendências , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
6.
Nat Commun ; 11(1): 5485, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127883

RESUMO

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Aprendizado de Máquina , Organoides/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Desenvolvimento de Medicamentos/métodos , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Organoides/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transcriptoma , Bexiga Urinária/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
7.
AAPS J ; 22(6): 135, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33098040

RESUMO

The microsampling workshop generated recommendations pertaining to blood sampling site (venous blood versus capillary blood), when to conduct a bridging study, statistical approaches to establish correlation/concordance and deciding on sample size, opportunities and challenges with patient-centric sampling, and how microsampling technology can enrich clinical drug development. Overall, the goal was to provide clarity and recommendations and enable the broader adoption of microsampling supporting patients' needs, convenience, and the transformation from clinic-centric to patient-centric drug development. The need and adoption of away-from-clinic sampling techniques has become critical to maintain patient safety during the current COVID-19 pandemic.


Assuntos
Coleta de Amostras Sanguíneas , Assistência Centrada no Paciente , Desenvolvimento de Medicamentos , Humanos
9.
Lancet Oncol ; 21(10): e488-e494, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002444

RESUMO

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.


Assuntos
Protocolos de Ensaio Clínico como Assunto , Oncologia/normas , Medidas de Resultados Relatados pelo Paciente , Antineoplásicos/uso terapêutico , Interpretação Estatística de Dados , Desenvolvimento de Medicamentos/legislação & jurisprudência , Desenvolvimento de Medicamentos/normas , Humanos , Comunicação Interdisciplinar , Oncologia/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa/normas
11.
Sci Transl Med ; 12(568)2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33077678

RESUMO

Rapid development of an efficacious vaccine against the viral pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of the coronavirus disease 2019 (COVID-19) pandemic, is essential, but rigorous studies are required to determine the safety of candidate vaccines. Here, on behalf of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group, we evaluate research on the potential risk of immune enhancement of disease by vaccines and viral infections, including coronavirus infections, together with emerging data about COVID-19 disease. Vaccine-associated enhanced disease has been rarely encountered with existing vaccines or viral infections. Although animal models of SARS-CoV-2 infection may elucidate mechanisms of immune protection, we need observations of enhanced disease in people receiving candidate COVID-19 vaccines to understand the risk of immune enhancement of disease. Neither principles of immunity nor preclinical studies provide a basis for prioritizing among the COVID-19 vaccine candidates with respect to safety at this time. Rigorous clinical trial design and postlicensure surveillance should provide a reliable strategy to identify adverse events, including the potential for enhanced severity of COVID-19 disease, after vaccination.


Assuntos
Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Animais , Ensaios Clínicos como Assunto , Infecções por Coronavirus/prevenção & controle , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Humanos , Pandemias , Vacinação
13.
Tex Med ; 116(10): 46, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33126267

RESUMO

Two federal agencies oversee the way vaccines reach the U.S. public. But only one of them guides physicians on the best way to use those vaccines. That agency is the Advisory Committee on Immunization Practices (ACIP), a branch of the U.S. Centers for Disease Control and Prevention. (The U.S. Food and Drug Administration regulates the way private companies develop and produce vaccines.).


Assuntos
Comitês Consultivos , Centers for Disease Control and Prevention, U.S. , Esquemas de Imunização , Educação de Pacientes como Assunto , Padrões de Prática Médica , Vacinas Virais , Infecções por Coronavirus/prevenção & controle , Desenvolvimento de Medicamentos , Humanos , Pandemias , Pneumonia Viral , Estados Unidos , Vacinação
15.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5343-5346, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019190

RESUMO

In-silico clinical platforms have been recently used as a new revolutionary path for virtual patients (VP) generation and further analysis, such as, drug development. Advanced individualized models have been developed to enhance flexibility and reliability of the virtual patient cohorts. This study focuses on the implementation and comparison of three different methodologies for generating virtual data for in-silico clinical trials. Towards this direction, three computational methods, namely: (i) the multivariate log-normal distribution (log- MVND), (ii) the supervised tree ensembles, and (iii) the unsupervised tree ensembles are deployed and evaluated against their performance towards the generation of high-quality virtual data using the goodness of fit (gof) and the dataset correlation matrix as performance evaluation measures. Our results reveal the dominance of the tree ensembles towards the generation of virtual data with similar distributions (gof values less than 0.2) and correlation patterns (average difference less than 0.03).


Assuntos
Cardiomiopatias , Árvores , Simulação por Computador , Desenvolvimento de Medicamentos , Humanos , Reprodutibilidade dos Testes
18.
Science ; 370(6512): 61-66, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004512

RESUMO

To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer's disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in the field. Here, we analyze the different forms of genetic risk of AD and how these can be used to model disease. We stress the importance of studying gene variants in the right cell types and in the right pathological context. The lack of mechanistic understanding of genetic variation has become the major bottleneck in the search for new drug targets for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Desenvolvimento de Medicamentos , Predisposição Genética para Doença , Pesquisa Médica Translacional , Doença de Alzheimer/prevenção & controle , Animais , Modelos Animais de Doenças , Variação Genética , Humanos , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Risco
19.
Yakugaku Zasshi ; 140(10): 1213-1224, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999200

RESUMO

In basic pharmaceutical sciences to achieve drug development, research on the efficient chemical synthesis of small molecules having cyclic skeletons is important. We have been engaged in the development of artificial catalysts for asymmetric ring formation reactions that exclusively synthesize right-handed or left-handed cyclic compounds and have achieved the construction of optically active cyclic skeletons using our original catalysts. The synthesis of biologically active compounds was facilitated through six-membered ring construction by Diels-Alder reaction of Danishefsky diene; however, no asymmetric variant of the reaction has been achieved. We approached this unresolved issue using multi-coordinated lanthanide metals. A new chiral lanthanide catalyst was developed, and the catalytic asymmetric Diels-Alder reaction of Danishefsky diene was realized for the first time. By modifying the chemical structure of Danishefsky diene, we applied the lanthanide catalyst to the syntheses of polycyclic compounds and biologically active compounds. We achieved the asymmetric synthesis of natural products, antibacterial and antimalarial compounds, and an anti-obesity drug lead compound. Moreover, the novel catalyst exhibited higher performance than the previously reported ones. The latest generation of the catalyst can be handled stably in air at room temperature. Furthermore, we succeeded in the development of new catalysts by focusing on the properties of its metal precursors, such as nickel and indium, and achieved the construction of polycyclic skeletons by using these catalysts.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos Policíclicos/síntese química , Alcenos/química , Antibacterianos/síntese química , Fármacos Antiobesidade/síntese química , Antimaláricos/síntese química , Produtos Biológicos/síntese química , Catálise , Reação de Cicloadição , Desenvolvimento de Medicamentos , Índio , Elementos da Série dos Lantanídeos/química , Níquel , Estereoisomerismo
20.
Yakugaku Zasshi ; 140(10): 1225-1233, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999201

RESUMO

This article describes our stereoselective and site-selective chemical methods for exploiting cationic heterocycles as electron-withdrawing groups (EWGs). We envisioned that the phosphoramide N-H proton of a pyridyl phosphoramide 3 would be activated by the cationic pyridinium moiety that is formed upon protonation. The resulting imide-like N-H proton and the acidic pyridinium proton of the pyridinium phosphoramide 3⋅HX cooperate together, making 3⋅HX a highly acidic dual Brønsted acid. The catalytic ability of 3⋅HX was demonstrated in the development of the first asymmetric Diels-Alder reaction between 1-amide dienes and maleimides. Focusing on the activation of N-bromosuccinimide (NBS) because of its structural similarity to maleimides, the enantioselective bromolactonization of trisubstituted olefinic acids was accomplished utilizing pyridyl phosphoramide 3f as a Brønsted base catalyst bearing an acidic N-H proton. Lastly, our strategy for the site-selective acylation of polyol compounds is described. In our system, a pyridine aldoxime ester 10, used as a mild acylating reagent, was activated by a catalytic amount of Lewis acid via the inductive effect of the cationic pyridinium moiety. The resulting metal complex preferentially attracted the alcohol with a Lewis basic site, thereby facilitating selective acylation via a template effect. This metal-template-driven strategy allowed for the site-selective acylation of diverse α-hydroxyamides, including unprotected N-glycolyl aminosugars.


Assuntos
Cátions/química , Cátions/síntese química , Química Orgânica/métodos , Desenvolvimento de Medicamentos/métodos , Elétrons , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Acilação , Amidas/química , Catálise , Complexos de Coordenação/química , Reação de Cicloadição , Ésteres/química , Compostos de Pralidoxima/química , Estereoisomerismo
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