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1.
Sci Rep ; 10(1): 14290, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868801

RESUMO

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Descoberta de Drogas , Pneumonia Viral/virologia , Amidas/química , Amidas/farmacologia , Antivirais/química , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/diagnóstico , Descoberta de Drogas/métodos , Humanos , Lopinavir/química , Lopinavir/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pandemias , Pneumonia Viral/diagnóstico , Pirazinas/química , Pirazinas/farmacologia , Ritonavir/química , Ritonavir/farmacologia
2.
Mol Cell ; 79(5): 710-727, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32853546

RESUMO

The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Genoma Viral , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , RNA Viral/genética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/uso terapêutico , Amidas/química , Amidas/uso terapêutico , Antivirais/química , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Pneumonia Viral/virologia , Pirazinas/química , Pirazinas/uso terapêutico , RNA Viral/antagonistas & inibidores , RNA Viral/metabolismo , Ribonucleosídeos/química , Ribonucleosídeos/uso terapêutico , Índice de Gravidade de Doença , Transcrição Genética , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
4.
RMD Open ; 6(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32763956

RESUMO

Reactive arthritis (ReA) is typically preceded by sexually transmitted disease or gastrointestinal infection. An association has also been reported with bacterial and viral respiratory infections. Herein, we report the first case of ReA after the he severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This male patient is in his 50s who was admitted with COVID-19 pneumonia. On the second day of admission, SARS-CoV-2 PCR was positive from nasopharyngeal swab specimen. Despite starting standard dose of favipiravir, his respiratory condition deteriorated during hospitalisation. On the fourth hospital day, he developed acute respiratory distress syndrome and was intubated. On day 11, he was successfully extubated, subsequently completing a 14-day course of favipiravir. On day 21, 1 day after starting physical therapy, he developed acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis. Arthrocentesis of his left ankle revealed mild inflammatory fluid without monosodium urate or calcium pyrophosphate crystals. Culture of synovial fluid was negative. Plain X-rays of his ankles and feet showed no erosive changes or enthesophytes. Tests for syphilis, HIV, anti-streptolysin O (ASO), Mycoplasma, Chlamydia pneumoniae, antinuclear antibody, rheumatoid factor, anticyclic citrullinated peptide antibody and Human Leukocyte Antigen-B27 (HLA-B27) were negative. Gonococcal and Chlamydia trachomatis urine PCR were also negative. He was diagnosed with ReA. Nonsteroidal Anti-Inflammatory Drug (NSAID)s and intra-articular corticosteroid injection resulted in moderate improvement.


Assuntos
Articulação do Tornozelo/diagnóstico por imagem , Artrite Reativa/diagnóstico , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/terapia , Corticosteroides/uso terapêutico , Amidas/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/uso terapêutico , Artrite Reativa/tratamento farmacológico , Artrite Reativa/etiologia , Artrocentese , Betacoronavirus , Infecções por Coronavirus/complicações , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pirazinas/uso terapêutico , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/complicações
5.
J Assoc Physicians India ; 68(8): 91-92, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32738849

Assuntos
Antivirais , Pirazinas , Amidas
6.
Mymensingh Med J ; 29(3): 747-754, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32844821

RESUMO

The sudden outbreak of a novel coronavirus in 2019 in Wuhan, China, that rapidly provoked a global concern, marked as the third attack of corona virus in the human society that affected the global healthcare system as well as the global economy. Until and unless an effective vaccine is discovered against the virus, the pharmacological intervention by different antivirals is in the run for remedy. The aim of this systematic review was to evaluate the role of favipiravir along with its safety and efficacy for the patients who are suffering from severe acute respiratory distress syndrome due to CoronaVirus-2 (SARS-CoV-2) as re-purposeful use. We searched PubMed, EMBASE for randomized controlled trials (RCTs), cilicaltrial.com for registered on going trails to evaluate the pros and cons of using favipiravir in COVID-19. After vigorous searching, screening and sorting of 314 articles for completed and published scientific evidences in electronic database, there were only 2 completed and published randomized control trials (RCT) and 17 ongoing or unpublished trials found until June 2020. The main outcome measures were viral clearance, clinical improvement and adverse events reported and published on 147 patients infected with SARS-CoV2. The 2 completed RCTs showed significantly better treatment effects on disease progression, viral clearance, improved the latency to relief for pyrexia and cough on favipiravir treated patients. Adverse effects caused Favipiravir are mild and manageable. Although 9 more RCTs and cohort studies are supposed to be completed by this time that may unveil some evidence for use of anti-RNA-viral drug favipiravir against influenza or Ebola to re-purposing against COVID-19 as adopted in different treatment guidelines.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , Betacoronavirus , China , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Resultado do Tratamento
8.
BMJ Open ; 10(7): e039730, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737100

RESUMO

INTRODUCTION: An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was reported in Wuhan, China, in mid-December 2019, and declared a pandemic by the WHO on 11 March 2020. Due to the unknown nature of the disease and the lack of specific drugs, several potential treatments were used for patients. This systematic review and meta-analysis will evaluate studies of the effects of favipiravir in COVID-19 pneumonia. METHODS AND ANALYSIS: We will search electronic databases including LitCovid hub, PubMed, Scopus, ISI Web of Sciences, Cochrane and Embase using keywords related to COVID-19 and favipiravir. We will search the reference lists of all included studies and reviews. We will also search for clinical trial registries, such as ClinicalTrials.gov, for the ongoing clinical trials. All randomised clinical trials investigating the safety and efficacy of favipiravir compared with other control groups for the treatment of patients with confirmed infection with SARS-CoV-2 will be included. Patients' survival at the end of the treatment as well as the follow-up will be the primary outcome of the treatment, followed by the time and rate of the patient with a negative COVID-19 test. The desired secondary outcome will consist of a decreased rate of symptoms, proportion of intensive care unit (ICU) transfers, length of the hospital stay, ICU treatments, the quality of life and additional adverse events. Data synthesis will be conducted using CMA V.2. Two independent investigators will be screening titles, abstracts and full texts of included studies, based on eligibility criteria. These investigators will then independently extract the data and appraise the quality of said studies. All potential discrepancies will be resolved through consultation with the third reviewer. Statistical heterogeneity will be assessed using a standard I2 test. A funnel plot, Egger's test and Begg's test will be used for detecting asymmetry to explore possible publication bias. ETHICS AND DISSEMINATION: All findings of this systematic review and meta-analysis will help identify the safety and efficacy of favipiravir for patients with COVID-19. Given that the design of the study is a systematic review, there is no need to follow the code of ethics protocol. The results of this study will be published in a reputable journal. PROSPERO REGISTRATION NUMBER: CRD42020180032.


Assuntos
Amidas , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Pirazinas , Adulto , Amidas/administração & dosagem , Amidas/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Masculino , Metanálise como Assunto , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etiologia , Pneumonia Viral/fisiopatologia , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Resultado do Tratamento
9.
Int J Med Sci ; 17(12): 1803-1810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714083

RESUMO

Since the end of 2019, a new type of coronavirus pneumonia (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading rapidly throughout the world. Previously, there were two outbreaks of severe coronavirus caused by different coronaviruses worldwide, namely Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). This article introduced the origin, virological characteristics and epidemiological overview of SARS-CoV-2, reviewed the currently known drugs that may prevent and treat coronavirus, explained the characteristics of the new coronavirus and provided novel information for the prevention and treatment of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Cloroquina/análogos & derivados , Cloroquina/uso terapêutico , Clorpromazina/uso terapêutico , Coronavirus/genética , Infecções por Coronavirus/genética , Ciclofilinas/antagonistas & inibidores , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Medicamentos de Ervas Chinesas/uso terapêutico , Endocitose/efeitos dos fármacos , Humanos , Soros Imunes , Indutores de Interferon/uso terapêutico , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Pneumonia Viral/genética , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Vacinas Virais/uso terapêutico
10.
BMJ Case Rep ; 13(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611659

RESUMO

Since December 2019, coronavirus disease 2019 (COVID-19) has been an international public health emergency. The possibility of COVID-19 should be considered primarily in patients with new-onset fever or respiratory tract symptoms. However, these symptoms can occur with other viral respiratory illnesses. We reported a case of severe acute respiratory syndrome coronavirus 2 and influenza A virus coinfection. During the epidemic, the possibility of COVID-19 should be considered regardless of positive findings for other pathogens.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Vírus da Influenza A/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/diagnóstico , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Amidas/uso terapêutico , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Coinfecção , Infecções por Coronavirus/tratamento farmacológico , Diagnóstico Diferencial , Glucocorticoides/uso terapêutico , Humanos , Influenza Humana/economia , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico , Pregnenodionas/uso terapêutico , Pirazinas/uso terapêutico , Radiografia , Reação em Cadeia da Polimerase em Tempo Real
12.
Plant Dis ; 104(9): 2338-2345, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32697657

RESUMO

Grape production is increasing globally and so are problems with downy mildew, one of the main constraints in grape production. Downy mildew on grape is caused by Plasmopara viticola, an obligate biotrophic pathogen belonging to the oomycetes. Control of the disease is usually performed by fungicide applications, of which carboxylic acid amide (CAA) fungicides represent one of the most widely used groups of fungicides. Our previous research showed that the extensive application of CAA fungicides can result in fungicide resistance and in China, CAA-resistant isolates of P. viticola were collected from the field in 2014. To monitor the distribution and spread of CAA fungicide resistance, we developed a TaqMan-minor groove binder (MGB) real-time PCR-based method designed on a functional mutation in the PvCesA3 gene that allows efficient identification of CAA fungicide resistant and sensitive genotypes. The assay was validated on 50 isolates using Sanger sequencing and fungicide bioassays and exploited in a comprehensive survey comprising 2,227 single-sporangiophore isolates from eight major grapevine regions in China. We demonstrate that CAA fungicide resistance in P. viticola is widespread in China. On average, 53.3% of the isolates were found to be resistant, but marked differences were found between locations with percentages of resistant isolates varying from 0.3 to 96.6%. Furthermore, the frequency of CAA-resistant isolates was found to be significantly correlated with the exposure to CAA fungicides (P < 0.05). We further discussed the possibilities to apply the TaqMan-MGB real-time PCR assay to assess the frequency of fungicide-resistant P. viticola isolates in each region or vineyard, which would facilitate the correct choice of fungicide for grape downy mildew and resistance management strategies.


Assuntos
Farmacorresistência Fúngica , Oomicetos/genética , Amidas , Ácidos Carboxílicos , China , Reação em Cadeia da Polimerase em Tempo Real
13.
Artigo em Inglês | MEDLINE | ID: mdl-32631826

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted the repurposing of drugs on the basis of promising in vitro and therapeutic results with other human coronavirus diseases, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). These repurposed drugs have mainly included remdesivir, favipiravir, lopinavir-ritonavir, ribavirin, interferons, and hydroxychloroquine. Unfortunately, the first open-label, randomized, controlled trials are showing poor efficacy of these repurposed drugs. These results highlight the necessity of identifying and characterizing specific and potent SARS-CoV-2 antivirals.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferons/uso terapêutico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Esquema de Medicação , Combinação de Medicamentos , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/uso terapêutico , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Pirazinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do Tratamento
14.
Biomolecules ; 10(7)2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679775

RESUMO

Therapeutic strategies for the treatment of any severe disease are based on the discovery and validation of druggable targets. The human genome encodes only 600-1500 targets for small-molecule drugs, but posttranslational modifications lead to a considerably larger druggable proteome. The spontaneous conversion of asparagine (Asn) residues to aspartic acid or isoaspartic acid is a frequent modification in proteins as part of the process called deamidation. Triosephosphate isomerase (TIM) is a glycolytic enzyme whose deamidation has been thoroughly studied, but the prospects of exploiting this phenomenon for drug design remain poorly understood. The purpose of this study is to demonstrate the properties of deamidated human TIM (HsTIM) as a selective molecular target. Using in silico prediction, in vitro analyses, and a bacterial model lacking the tim gene, this study analyzed the structural and functional differences between deamidated and nondeamidated HsTIM, which account for the efficacy of this protein as a druggable target. The highly increased permeability and loss of noncovalent interactions of deamidated TIM were found to play a central role in the process of selective enzyme inactivation and methylglyoxal production. This study elucidates the properties of deamidated HsTIM regarding its selective inhibition by thiol-reactive drugs and how these drugs can contribute to the development of cell-specific therapeutic strategies for a variety of diseases, such as COVID-19 and cancer.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Triose-Fosfato Isomerase/antagonistas & inibidores , Amidas/antagonistas & inibidores , Amidas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Mutação , Pandemias , Proteoma/antagonistas & inibidores , Proteoma/genética , Proteoma/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequenas/química , Triose-Fosfato Isomerase/química , Triose-Fosfato Isomerase/metabolismo
15.
Eur J Cancer ; 136: 1-3, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610172
17.
J Nanosci Nanotechnol ; 20(12): 7311-7323, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32711596

RESUMO

We started a study on the molecular docking of six potential pharmacologically active inhibitors compounds that can be used clinically against the COVID-19 virus, in this case, remdesivir, ribavirin, favipiravir, galidesivir, hydroxychloroquine and chloroquine interacting with the main COVID-19 protease in complex with a COVID-19 N3 protease inhibitor. The highest values of affinity energy found in order from highest to lowest were chloroquine (CHL), hydroxychloroquine (HYC), favipiravir (FAV), galidesivir (GAL), remdesivir (REM) and ribavirin (RIB). The possible formation of hydrogen bonds, associations through London forces and permanent electric dipole were analyzed. The values of affinity energy obtained for the hydroxychloroquine ligands was -9.9 kcal/mol and for the chloroquine of -10.8 kcal/mol which indicate that the coupling contributes to an effective improvement of the affinity energies with the protease. Indicating that, the position chosen to make the substitutions may be a pharmacophoric group, and cause changes in the protease.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/química , Adenina/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Amidas/administração & dosagem , Amidas/química , Amidas/farmacologia , Antivirais/administração & dosagem , Sítios de Ligação , Cloroquina/administração & dosagem , Cloroquina/química , Cloroquina/farmacologia , Interações Medicamentosas , Humanos , Ligação de Hidrogênio , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Nanotecnologia , Pandemias , Inibidores de Proteases/administração & dosagem , Pirazinas/administração & dosagem , Pirazinas/química , Pirazinas/farmacologia , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Pirrolidinas/farmacologia , Ribavirina/administração & dosagem , Ribavirina/química , Ribavirina/farmacologia , Eletricidade Estática
18.
Int J Mol Sci ; 21(11)2020 May 30.
Artigo em Inglês | MEDLINE | ID: covidwho-437471

RESUMO

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2'-Fluoro-2'-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (-7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity -6.06 and -4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.


Assuntos
Antivirais/farmacologia , Cisteína Endopeptidases/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/química , Amidas/química , Amidas/farmacologia , Amodiaquina/química , Amodiaquina/farmacologia , Antivirais/química , Sítios de Ligação , Cisteína Endopeptidases/metabolismo , Inibidores de Proteases/química , Ligação Proteica , Pirazinas/química , Pirazinas/farmacologia , Ribavirina/química , Ribavirina/farmacologia , Proteínas não Estruturais Virais/metabolismo
19.
Tohoku J Exp Med ; 251(2): 87-90, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-593619

RESUMO

In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.


Assuntos
Amidas/efeitos adversos , Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hiperuricemia/induzido quimicamente , Pneumonia Viral/tratamento farmacológico , Pirazinas/efeitos adversos , Ácido Úrico/sangue , Aldeído Oxidase/metabolismo , Amidas/farmacocinética , Amidas/urina , Antivirais/farmacocinética , Biotransformação , Interações Medicamentosas , Humanos , Hiperuricemia/fisiopatologia , Rim/metabolismo , Nefropatias/metabolismo , Estrutura Molecular , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Pandemias , Pirazinas/farmacocinética , Pirazinas/urina , Xantina Oxidase/metabolismo
20.
Trials ; 21(1): 488, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503657

RESUMO

OBJECTIVES: A variety of possible mechanisms can make the nucleic acid test of patients who meet the discharge conditions positive again, including reinfection, reactivation of the original virus, lack of strict discharge criteria, new infection, and so on. Different reasons will correspond to different prevention and control measures. We will enroll patients who are discharged after treatment, whose nucleic acid test has changed from negative to positive during the screening visit, regardless of the severity of the symptoms, to investigate the mechanism, clinical outcome and therapeutic efficacy with Favipiravir patients with Corona virus Disease 2019. Favipiravir is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase, it has been used for treatment of some life-threatening infections such as Ebola virus, Lassa virus and rabies. Its therapeutic efficacy has been proven in these diseases. TRIAL DESIGN: This is a multi-center, two arm, open label, parallel group, randomized controlled trial. PARTICIPANTS: Eligibility criteria: Inclusion criteria: 1.Adults 18 to 80 years, male or female.2.After the first diagnosis and treatment of COVID-19, the nucleic acid test of respiratory specimens such as sputum or nasopharyngeal swabs, has been negative for two consecutive times (sampling time interval of at least 24 hours), in accordance with the COVID-19's diagnosis and treatment Plan (7th Edition), discharged.3.During screening visit (follow-up after discharge), The nucleic acid test of COVID-19 is positive in any one of the following samples: sputum, throat swabs, blood, feces or other specimens. Regardless of whether or not they had symptoms and the severity of symptoms.4.Volunteer to participate in the research and sign the Informed Consent Form. EXCLUSION CRITERIA: 1.Allergic to Favipiravjr;2.Pregnant or lactating women3.Uncontrolled diseases of the blood and cardiovascular system, liver or kidney.4.History of mental disorders, drug abuse or dependence;5.Researchers consider it inappropriate for adults to participate;6.Participating in other clinical studies. Loss to Follow up: Cases that do not complete the clinical trial program will be regarded as lost to follow up. Including the withdrawal of patients by themselves (such as poor compliance, etc.), or the withdrawal of patients ordered by the researcher (those who need other drugs which affect the judgment of the curative effect, and those who need to stop taking drugs for severe adverse events) Study setting: The participating hospitals are some of the designated hospitals that have been or may be admitting patients who meet the eligibility criteria, mainly in Hubei, Shenzhen, Anhui and Beijing. Participants will be recruited from these 15 hospitals: Wuhan Pulmonary Hospital, Hubei; Jinyintan Hospital of Wuhan, Hubei; Ezhou Central Hospital, Hubei; The Second People's Hospital of Fuyang, Anhui; The First Affiliated Hospital of USTC, Anhui; Beijing Youan Hospital, Beijing; Capital Medical University Beijing Institute of Hepatology, Beijing; Ezhou Hospital of Traditional Chinese Medicine, Hubei; Zhongnan Hospital of Wuhan University, Hubei; The Fifth Hospital of ShiJiazhuang, Hebei; Jinan Infectious Diseases Hospital, Shandong; Public Health Clinical Center of Chengdu, Sichuan; Wuxi No.5 People's Hospital, Jiangsu; The Third People's Hospital of Shenzhen, Guangdong; The First Affiliated Hospital of Bengfu Medical College, AnHui. INTERVENTION AND COMPARATOR: Favipiravir group (experimental): Favipiravir 1600mg each dose, twice a day on the 1st day; 600mg each dose, twice a day from the 2nd to the 7th day, Oral administration, the maximum number of days taken will be no more than 14 days plus routine treatment for COVID-19. Regular treatment group (control): Treatments other than Antiviral drugs can be given. Routine treatment for patients with the corona virus will be administered, this includes oxygen therapy, drugs that reduced phlegm and relieve cough, including thymosin, proprietary Chinese medicine, etc. MAIN OUTCOMES: Primary Outcome Measures: Viral nucleic acid test negative [Time Frame: 5 months]: Subjects who tested negative for nucleic acid from sputum or nasopharyngeal swabs for two consecutive times (sampling time interval of at least 24 hours). SECONDARY OUTCOME MEASURES: Clinical cure [Time Frame: 5 months]: 1.Body temperature returned to normal for more than 3 days;2.Lung image improved.3.Clinical manifestation improved;4.The viral nucleic acid test of respiratory specimens was negative for two consecutive times (sampling time interval of at least 24 hours). RANDOMIZATION: The central randomization system (Interactive Web Response Management System), will be used to randomly divide the subjects into the experimental group and the control group according to the ratio of 2:1. In this study, block randomization will be used, in blocks of 6. BLINDING (MASKING): This is an open label trial. Trial participants, investigators, care givers, outcome assessors, and date analysts are not blinded to group assignment. NUMBERS TO BE RANDOMISED: 210 patients are expected to be enrolled and allocated according to the ratio of 2 (Favipiravir group, n=140): 1(regular treatment group, n=70). TRIAL STATUS: Protocol version number 3.0, 10th April 2020 First Patient, first visit 17th March 2020; recruitment end date anticipated June 1, 2020. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04333589, April 3, 2020. Registered April 3, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , RNA Viral/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/genética , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/virologia , Resultado do Tratamento , Adulto Jovem
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