Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.781
Filtrar
1.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800013

RESUMO

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.


Assuntos
Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Disponibilidade Biológica , Biologia Computacional/métodos , Bases de Dados de Compostos Químicos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Metiltransferases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Plantas Medicinais/química , Ligação Proteica , Domínios Proteicos/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , RNA Helicases/química , Relação Estrutura-Atividade , Termodinâmica , Proteínas não Estruturais Virais/química
2.
Molecules ; 26(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801151

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.


Assuntos
Aloe/química , Antivirais/análise , Antivirais/química , Desenvolvimento de Medicamentos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Antivirais/metabolismo , Antivirais/farmacocinética , Biologia Computacional , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacocinética , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
3.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805419

RESUMO

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.


Assuntos
Antivirais/farmacocinética , Reposicionamento de Medicamentos/métodos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Antivirais/sangue , Medicamentos Biossimilares , Bloqueadores dos Canais de Cálcio/farmacocinética , Simulação por Computador , Bases de Dados de Produtos Farmacêuticos , Desenvolvimento de Medicamentos/métodos , Humanos , Hipertensão Pulmonar/virologia , Distribuição Tecidual
4.
J Med Chem ; 64(8): 5001-5017, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33835812

RESUMO

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Pró-Fármacos/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Células CACO-2 , Células Cultivadas , Chlorocebus aethiops , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Células Epiteliais/virologia , Humanos , Macaca fascicularis , Masculino , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Infecções por Vírus Respiratório Sincicial/virologia , Relação Estrutura-Atividade , Distribuição Tecidual , Tubercidina/análogos & derivados , Tubercidina/química , Carga Viral
5.
CNS Drugs ; 35(4): 345-384, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33866523

RESUMO

As many patients with underlying psychiatric disorders may be infected with COVID-19, and COVID-19-affected subjects may frequently experience a new onset of psychiatric manifestations, concomitant use of psychotropic medications and COVID-19 therapies is expected to be highly likely and raises concerns of clinically relevant drug interactions. In this setting, four major mechanisms responsible for drug interactions involving psychotropic agents and COVID-19 therapies may be identified: (1) pharmacokinetic drug-drug interactions mainly acting on cytochrome P450; (2) pharmacodynamic drug-drug interactions resulting in additive or synergistic toxicity; (3) drug-disease interactions according to stage and severity of the disease; and (4) pharmacogenetic issues associated with polymorphisms of cytochrome P450 isoenzymes. In this review, we summarise the available literature on relevant drug interactions between psychotropic agents and COVID-19 therapies, providing practical clinical recommendations and potential management strategies according to severity of illness and clinical scenario.


Assuntos
/tratamento farmacológico , Reposicionamento de Medicamentos/tendências , Transtornos Mentais/metabolismo , Psicotrópicos/efeitos adversos , Psicotrópicos/metabolismo , Antivirais/efeitos adversos , Antivirais/farmacocinética , /metabolismo , Interações Medicamentosas/fisiologia , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Farmacogenética/tendências
6.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808940

RESUMO

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 µM and 99% at 15 µM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 µM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.


Assuntos
Antivirais/química , Antivirais/farmacologia , Oxisteróis/química , Oxisteróis/farmacologia , /efeitos dos fármacos , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Camundongos , Proteínas do Nucleocapsídeo/efeitos dos fármacos , Oxisteróis/administração & dosagem , Oxisteróis/farmacocinética , Células Vero , Replicação Viral/efeitos dos fármacos
7.
Emerg Microbes Infect ; 10(1): 481-492, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33691601

RESUMO

The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.


Assuntos
Antivirais/farmacologia , /antagonistas & inibidores , Sistema Respiratório/virologia , /efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Quimioterapia Combinada , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Pró-Fármacos/farmacologia , Ratos , Ratos Sprague-Dawley , Células Vero
8.
Peptides ; 139: 170526, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33676968

RESUMO

The Coronaviridae family comprises large enveloped single-stranded RNA viruses. The known human-infecting coronaviruses; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), novel SARS-CoV-2, human coronavirus (HCoV)-NL63, HCoV-229E, HCoV-OC43 and HKU1 cause mild to severe respiratory infections. The viral diseases induced by mammalian and avian viruses from Coronaviridae family pose significant economic and public health burdens. Due to increasing reports of viral resistance, co-infections and the emergence of viral epidemics such as COVID-19, available antiviral drugs show low or no efficacy, and the production of new treatments or vaccines are also challenging. Therefore, demand for the development of novel antivirals has considerably increased. In recent years, antiviral peptides have generated increasing interest as they are from natural and computational sources, are highly specific and effective, and possess the broad-spectrum activity with minimum side effects. Here, we have made an effort to compile and review the antiviral peptides with activity against Coronaviridae family viruses. They were divided into different categories according to their action mechanisms, including binding/attachment inhibitors, fusion and entry inhibitors, viral enzyme inhibitors, replication inhibitors and the peptides with direct and indirect effects on the viruses. Reported studies suggest optimism with regard to the design and production of therapeutically promising antiviral drugs. This review aims to summarize data relating to antiviral peptides particularly with respect to their applicability for development as novel treatments.


Assuntos
Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , Peptídeos/farmacologia , Antivirais/farmacocinética , Peptídeos/farmacocinética , Internalização do Vírus/efeitos dos fármacos
9.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670304

RESUMO

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Lisossomos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antivirais/farmacocinética , Antivirais/uso terapêutico , /metabolismo , Clorpromazina/farmacocinética , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Fluvoxamina/farmacocinética , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Interleucina-1/antagonistas & inibidores , Interleucina-1/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Lisossomos/imunologia , Lisossomos/metabolismo , Lisossomos/virologia , /fisiologia , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Replicação Viral/efeitos dos fármacos
10.
Bioorg Med Chem Lett ; 39: 127885, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662537

RESUMO

Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC50 < 0.25 µM) and anti-MERS-CoV activities (IC50 < 1.1 µM) with no cytotoxicity (CC50 > 25 µM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies.


Assuntos
Antivirais/síntese química , Desenho de Fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinazolinonas/farmacologia , /efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/uso terapêutico , /virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/uso terapêutico , Ratos , Relação Estrutura-Atividade
11.
mSphere ; 6(1)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536322

RESUMO

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [C max]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.


Assuntos
Citosina/análogos & derivados , Vírus da Varíola dos Macacos/efeitos dos fármacos , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Varíola/tratamento farmacológico , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Citosina/farmacocinética , Citosina/farmacologia , Modelos Animais de Doenças , Cães , Feminino , Isoindóis/farmacocinética , Isoindóis/farmacologia , Masculino , Vírus da Varíola/efeitos dos fármacos
12.
Clin Drug Investig ; 41(2): 133-147, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33527237

RESUMO

BACKGROUND: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. METHODS: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. RESULTS: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. CONCLUSIONS: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.


Assuntos
Amidas/farmacocinética , Antivirais/farmacocinética , Benzofuranos/farmacocinética , Carbamatos/farmacocinética , Ciclopropanos/farmacocinética , Imidazóis/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Atorvastatina/farmacocinética , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pravastatina/farmacocinética , Quinolinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto Jovem
13.
Commun Biol ; 4(1): 193, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33564093

RESUMO

SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site. Our findings provide new insights for the development of uracil scaffold-based drugs.


Assuntos
Antivirais/farmacologia , /virologia , Endorribonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinas/farmacologia , /enzimologia , Timina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Células A549 , Antivirais/química , Antivirais/farmacocinética , Domínio Catalítico , Cristalografia por Raios X , Endorribonucleases/química , Endorribonucleases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Timina/química , Timina/farmacocinética , Uridina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
15.
Clin Pharmacol Ther ; 109(4): 1030-1033, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33547636

RESUMO

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.


Assuntos
Antivirais/farmacocinética , Lopinavir/farmacocinética , Plasma/fisiologia , Ligação Proteica/fisiologia , Idoso , Albuminas/metabolismo , Antivirais/uso terapêutico , Proteína C-Reativa/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga Viral
16.
Arch Biochem Biophys ; 700: 108771, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33485847

RESUMO

In the current study, a structure-based virtual screening paradigm was used to screen a small molecular database against the Non-structural protein 15 (Nsp15) endoribonuclease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is the causative agent of the recent outbreak of coronavirus disease 2019 (COVID-19) which left the entire world locked down inside the home. A multi-step molecular docking study was performed against antiviral specific compounds (~8722) collected from the Asinex antiviral database. The less or non-interacting molecules were wiped out sequentially in the molecular docking. Further, MM-GBSA based binding free energy was estimated for 26 compounds which shows a high affinity towards the Nsp15. The drug-likeness and pharmacokinetic parameters of all 26 compounds were explored, and five molecules were found to have an acceptable pharmacokinetic profile. Overall, the Glide-XP docking score and Prime-MM-GBSA binding free energy of the selected molecules were explained strong interaction potentiality towards the Nsp15 endoribonuclease. The dynamic behavior of each molecule with Nsp15 was assessed using conventional molecular dynamics (MD) simulation. The MD simulation information was strongly favors the Nsp15 and each identified ligand stability in dynamic condition. Finally, from the MD simulation trajectories, the binding free energy was estimated using the MM-PBSA method. Hence, the proposed final five molecules might be considered as potential Nsp15 modulators for SARS-CoV-2 inhibition.


Assuntos
Antivirais/farmacologia , /virologia , Endorribonucleases/antagonistas & inibidores , /enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacocinética , Bases de Dados de Compostos Químicos , Avaliação Pré-Clínica de Medicamentos , Endorribonucleases/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Técnicas In Vitro , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Interface Usuário-Computador , Proteínas não Estruturais Virais/química
17.
Expert Opin Investig Drugs ; 30(3): 263-269, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33405993

RESUMO

BACKGROUND & AIMS: TQ-A3334, a selective, oral toll-like receptor (TLR)-7 agonist, is being developed to treat chronic hepatitis B (CHB). This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TQ-A3334 in healthy participants. RESEARCH DESIGN AND METHODS: The effects of a single-ascending dose of TQ-A3334 (0.2-1.8 mg) combined with food (1.2 mg) were evaluated in 48 healthy participants. RESULTS: No serious adverse events or discontinuations occurred in the study. The most common adverse reactions were lymphocyte count decreased and headache, which were generally consistent with IFN-α exposure and the mechanism of action of a TLR7 agonist. TQ-A3334 was rapidly absorbed, with a time to maximum plasma concentration of 0.42-0.5 h. Systemic exposure (Cmax and AUC) to TQ-A3334 increased with a slight saturation proportion to dose. Food reduced the exposure of TQ-A3334. The concentrations of MCP-1, ISG-15, MX-1, and OAS-1 were observed to be slightly dose-dependent, ranging from 1.0 to 1.8 mg TQ-A3334. CONCLUSIONS: Oral doses of 0.2-1.8 mg appeared to be safe and tolerated. PD activity was seen at doses ranging from 1.0 to 1.8 mg, indicating its possible future use to treat CHB. TRIAL REGISTRATION: The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20182248).


Assuntos
Antivirais/administração & dosagem , Interações Alimento-Droga , Receptor 7 Toll-Like/agonistas , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino
18.
Clin Pharmacol Ther ; 109(4): 1116-1124, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33501997

RESUMO

Severe coronavirus disease 2019 (COVID-19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically-based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady-state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult phase I exposure data in healthy volunteers who were administered a 200-mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100-mg daily maintenance doses of IV over 0.5 hours starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200-mg loading dose on Day 1 then 100-mg daily maintenance dose starting on Day 2) in pediatric patients ≥ 40 kg and a weight-based remdesivir dosage regimen (5-mg/kg loading dose on Day 1 then 2.5-mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 to < 40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support remdesivir as a treatment option during the pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Antivirais/farmacocinética , /tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/administração & dosagem , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/uso terapêutico , Área Sob a Curva , Peso Corporal , Criança , Pré-Escolar , Simulação por Computador , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lactente , Masculino , Modelos Biológicos , Pandemias
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119388, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33503560

RESUMO

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded NH⋯O intermolecular interactions and two weak hydrogen bonded CH⋯O interactions. The red shift in NH stretching frequency exposed from IR substantiates the formation of NH⋯O intermolecular hydrogen bond and the blue shift in CH stretching frequency substantiates the formation of CH⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.


Assuntos
Antivirais , Cromonas , Drogas em Investigação , Tioureia , Antivirais/análise , Antivirais/síntese química , Antivirais/química , Antivirais/farmacocinética , Cromonas/análise , Cromonas/síntese química , Cromonas/química , Cromonas/farmacocinética , Química Computacional , Cristalografia por Raios X , Drogas em Investigação/análise , Drogas em Investigação/síntese química , Drogas em Investigação/química , Drogas em Investigação/farmacocinética , Humanos , Hidrazinas/química , Hidrogênio/química , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Tioamidas/análise , Tioamidas/síntese química , Tioamidas/química , Tioamidas/farmacocinética , Tioureia/análise , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinética , Vibração
20.
Drug Discov Ther ; 14(6): 273-281, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33390567

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is undoubtedly the most challenging pandemic in the current century. A total of 73,953,702 confirmed cases of COVID-19 and 1,644,416 deaths were reported globally up to December 17, 2020. Therefore, in the absence of a safe and effective vaccine, it is urgent to identify a novel antiviral drug to effectively treat patients with COVID-19. On October 22, the U.S. Food and Drug Administration approved remdesivir, a nucleotide analog prodrug with broad antiviral activity, for adults and children (12 years of age and older and weighing at least 40 kg) who need to be admitted to hospital for covid-19 treatment. In order to monitor the optimization of patient clinical response profile, as well as address the challenges associated with remdesivir metabolism, highly sensitive, selective and accurate analytical methods are necessary. This review clearly covers all the analytical methods developed for the identification and quantitative determination of remdesivir and its metabolites in biological matrices, which helps the researchers in developing new methods for the analysis of remdesivir by considering the pros and cons of the previously reported methods.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/análise , Monitoramento de Medicamentos/métodos , Monofosfato de Adenosina/análise , Monofosfato de Adenosina/farmacocinética , Alanina/análise , Alanina/farmacocinética , Antivirais/farmacocinética , /virologia , Humanos , Valor Preditivo dos Testes , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...