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1.
Int J Mol Sci ; 23(10)2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35628472

RESUMO

Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.


Assuntos
COVID-19 , Conexinas , COVID-19/tratamento farmacológico , Conexinas/genética , Conexinas/metabolismo , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Inflamação , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro , Ritonavir
2.
Int J Mol Sci ; 23(9)2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35563409

RESUMO

Connexin43 (Cx43) hemichannels form a pathway for cellular communication between the cell and its extracellular environment. Under pathological conditions, Cx43 hemichannels release adenosine triphosphate (ATP), which triggers inflammation. Over the past two years, azithromycin, chloroquine, dexamethasone, favipiravir, hydroxychloroquine, lopinavir, remdesivir, ribavirin, and ritonavir have been proposed as drugs for the treatment of the coronavirus disease 2019 (COVID-19), which is associated with prominent systemic inflammation. The current study aimed to investigate if Cx43 hemichannels, being key players in inflammation, could be affected by these drugs which were formerly designated as COVID-19 drugs. For this purpose, Cx43-transduced cells were exposed to these drugs. The effects on Cx43 hemichannel activity were assessed by measuring extracellular ATP release, while the effects at the transcriptional and translational levels were monitored by means of real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunoblot analysis, respectively. Exposure to lopinavir and ritonavir combined (4:1 ratio), as well as to remdesivir, reduced Cx43 mRNA levels. None of the tested drugs affected Cx43 protein expression.


Assuntos
COVID-19 , Conexina 43 , Trifosfato de Adenosina/metabolismo , COVID-19/tratamento farmacológico , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Conexina 43/metabolismo , Humanos , Inflamação , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Ritonavir/farmacologia
3.
Biomed Pharmacother ; 150: 112999, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35461087

RESUMO

SLC2A1 mediates glucose cellular uptake; key to appropriate immune function. Our previous work has shown efavirenz and lopinavir exposure inhibits T cell and macrophage responses, to known agonists, likely via interactions with glucose transporters. Using human cell lines as a model, we assessed glucose uptake and subsequent bioenergetic profiles, linked to immunological responses. Glucose uptake was measured using 2-deoxyglucose as a surrogate for endogenous glucose, using commercially available reagents. mRNA expression of SLC transporters was investigated using qPCR TaqMan™ gene expression assay. Bioenergetic assessment, on THP-1 cells, utilised the Agilent Seahorse XF Mito Stress test. In silico analysis of potential interactions between SLC2A1 and antiretrovirals was investigated using bioinformatic techniques. Efavirenz and lopinavir exposure was associated with significantly lower glucose accumulation, most notably in THP-1 cells (up to 90% lower and 70% lower with efavirenz and lopinavir, respectively). Bioenergetic assessment showed differences in the rate of ATP production (JATP); efavirenz (4 µg/mL), was shown to reduce JATP by 87% whereas lopinavir (10 µg/mL), was shown to increase the overall JATP by 77%. Putative in silico analysis indicated the antiretrovirals, apart from efavirenz, associated with the binding site of highest binding affinity to SLC2A1, similar to that of glucose. Our data suggest a role for efavirenz and lopinavir in the alteration of glucose accumulation with subsequent alteration of bioenergetic profiles, supporting our hypothesis for their inhibitory effect on immune cell activation. Clarification of the implications of this data, for in vivo immunological responses, is now warranted to define possible consequences for these, and similar, therapeutics.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Trifosfato de Adenosina , Alcinos/uso terapêutico , Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Ciclopropanos , Metabolismo Energético , Glucose/uso terapêutico , Transportador de Glucose Tipo 1/genética , Infecções por HIV/tratamento farmacológico , Humanos , Lopinavir/farmacologia , Ritonavir
4.
Antiviral Res ; 202: 105311, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35390430

RESUMO

Nelfinavir is an HIV protease inhibitor that has been widely prescribed as a component of highly active antiretroviral therapy, and has been reported to exert in vitro antiviral activity against SARS-CoV-2. We here assessed the effect of Nelfinavir in a SARS-CoV-2 infection model in hamsters. Despite the fact that Nelfinavir, [50 mg/kg twice daily (BID) for four consecutive days], did not reduce viral RNA load and infectious virus titres in the lung of infected animals, treatment resulted in a substantial improvement of SARS-CoV-2-induced lung pathology. This was accompanied by a dense infiltration of neutrophils in the lung interstitium which was similarly observed in non-infected hamsters. Nelfinavir resulted also in a marked increase in activated neutrophils in the blood, as observed in non-infected animals. Although Nelfinavir treatment did not alter the expression of chemoattractant receptors or adhesion molecules on human neutrophils, in vitro migration of human neutrophils to the major human neutrophil attractant CXCL8 was augmented by this protease inhibitor. Nelfinavir appears to induce an immunomodulatory effect associated with increasing neutrophil number and functionality, which may be linked to the marked improvement in SARS-CoV-2 lung pathology independent of its lack of antiviral activity. Since Nelfinavir is no longer used for the treatment of HIV, we studied the effect of two other HIV protease inhibitors, namely the combination Lopinavir/Ritonavir (Kaletra™) in this model. This combination resulted in a similar protective effect as Nelfinavir against SARS-CoV2 induced lung pathology in hamsters.


Assuntos
COVID-19 , Infecções por HIV , Inibidores da Protease de HIV , Animais , COVID-19/tratamento farmacológico , Cricetinae , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pulmão , Mesocricetus , Nelfinavir/farmacologia , Nelfinavir/uso terapêutico , RNA Viral , Ritonavir/uso terapêutico , SARS-CoV-2
5.
J Biomol Struct Dyn ; 40(8): 3416-3427, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33200673

RESUMO

The exponential increase in cases and mortality of coronavirus disease (COVID-19) has called for a need to develop drugs to treat this infection. Using in silico and molecular docking approaches, this study investigated the inhibitory effects of Pradimicin A, Lamivudine, Plerixafor and Lopinavir against SARS-CoV-2 Mpro. ADME/Tox of the ligands, pharmacophore hypothesis of the co-crystalized ligand and the receptor, and docking studies were carried out on different modules of Schrodinger (2019-4) Maestro v12.2. Among the ligands subjected to ADME/Tox by QikProp, Lamivudine demonstrated drug-like physico-chemical properties. A total of five pharmacophore binding sites (A3, A4, R9, R10, and R11) were predicted from the co-crystalized ligand and the binding cavity of the SARS-CoV-2 Mpro. The docking result showed that Lopinavir and Lamivudine bind with a higher affinity and lower free energy than the standard ligand having a glide score of -9.2 kcal/mol and -5.3 kcal/mol, respectively. Plerixafor and Pradimicin A have a glide score of -3.7 kcal/mol and -2.4 kcal/mol, respectively, which is lower than the co-crystallized ligand with a glide score of -5.3 kcal/mol. Molecular dynamics confirmed that the ligands maintained their interaction with the protein with lower RMSD fluctuations over the trajectory period of 100 nsecs and that GLU166 residue is pivotal for binding. On the whole, present study specifies the repurposing aptitude of these molecules as inhibitors of SARS-CoV-2 Mpro with higher binding scores and forms energetically stable complexes with Mpro.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Compostos Heterocíclicos , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus , Mobilização de Células-Tronco Hematopoéticas , Humanos , Lamivudina , Ligantes , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2
6.
J Biomol Struct Dyn ; 40(8): 3711-3730, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33251975

RESUMO

Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (Mpro) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of Mpro and RdRp in vitro. Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of Mpro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the Mpro. Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards Mpro. In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19. Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Simulação de Dinâmica Molecular , Adipatos , Amidas , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Humanos , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Pirazinas , Relação Quantitativa Estrutura-Atividade , RNA , RNA Polimerase Dependente de RNA , SARS-CoV-2 , Succinatos
7.
J Cell Biochem ; 123(2): 347-358, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34741481

RESUMO

As per the World Health Organization report, around 226 844 344 confirmed positive cases and 4 666 334 deaths are reported till September 17, 2021 due to the recent viral outbreak. A novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is responsible for the associated coronavirus disease (COVID-19), which causes serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to combat the outbreak. Due to the emergency, the drug repurposing approach is being explored for COVID-19. In this study, we attempt to understand the potential mechanism and also the effect of the approved antiviral drugs against the SARS-CoV-2 main protease (Mpro). To understand the mechanism of inhibition of the malaria drug hydroxychloroquine (HCQ) against SARS-CoV-2, we performed molecular interaction studies. The studies revealed that HCQ docked at the active site of the Human ACE2 receptor as a possible way of inhibition. Our in silico analysis revealed that the three drugs Lopinavir, Ritonavir, and Remdesivir showed interaction with the active site residues of Mpro. During molecular dynamics simulation, based on the binding free energy contributions, Lopinavir showed better results than Ritonavir and Remdesivir.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Hidroxicloroquina/farmacologia , Lopinavir/farmacologia , Receptores Virais/efeitos dos fármacos , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/fisiologia , Antivirais/uso terapêutico , Sítios de Ligação , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/fisiologia , Conjuntos de Dados como Assunto , Reposicionamento de Medicamentos , Transferência de Energia , Humanos , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Receptores Virais/fisiologia , Ritonavir/uso terapêutico
8.
Chem Commun (Camb) ; 57(93): 12476-12479, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34734602

RESUMO

We identified small-molecule enhancers of cellular stress granules by observing molecular crowding of proteins and RNAs in a time-dependent manner. Hit molecules sensitized the IRF3-mediated antiviral mechanism in the presence of poly(I:C) and inhibited the replication of SARS-CoV-2 by inducing stress granule formation. Thus, modulating multimolecular crowding can be a promising strategy against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Benzopiranos/farmacologia , Grânulos Citoplasmáticos/efeitos dos fármacos , Pirazóis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Benzopiranos/química , Linhagem Celular Tumoral , Chlorocebus aethiops , Grânulos Citoplasmáticos/metabolismo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Fator Regulador 3 de Interferon/metabolismo , Lopinavir/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Poli I-C/farmacologia , Pirazóis/química , Relação Estrutura-Atividade , Células Vero
9.
PLoS Comput Biol ; 17(9): e1008363, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34491984

RESUMO

Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.


Assuntos
Farmacorresistência Viral/genética , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Lopinavir/farmacologia , Mutação , Teorema de Bayes , Estudos de Coortes , Infecções por HIV/virologia , HIV-1/classificação , Humanos
10.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502033

RESUMO

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Lactamas/farmacologia , Leucina/farmacologia , Nitrilas/farmacologia , Prolina/farmacologia , Antivirais/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/uso terapêutico , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
11.
Sci Rep ; 11(1): 17810, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497279

RESUMO

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antivirais/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Comorbidade , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Fígado/patologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Lopinavir/química , Lopinavir/metabolismo , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ritonavir/química , Ritonavir/metabolismo , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/isolamento & purificação , Especificidade por Substrato
12.
Pharmacol Rep ; 73(6): 1520-1538, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34458951

RESUMO

The global spread of COVID-19 has imparted significant economic, medical, and social burdens. Like adults, children are affected by this pandemic. However, milder clinical symptoms are often experienced by them. Only a minimal proportion of the affected patients may develop severe and complicated COVID-19. Supportive treatment is recommended in all patients. Antiviral and immunomodulatory medications are spared for hospitalized children with respiratory distress or severe to critical disease. Up till now, remdesivir is the only USFDA-approved anti-COVID-19 medication indicated in the majority of symptomatic patients with moderate to severe disease. Dexamethasone is solely recommended in patients with respiratory distress maintained on oxygen or ventilatory support. The use of these medications in pediatric patients is founded on evidence deriving from adult studies. No randomized controlled trials (RCTs) involving pediatric COVID-19 patients have assessed these medications' efficacy and safety, among others. Similarly, three novel monoclonal anti-SARS-CoV-2 spike protein antibodies, bamlanivimab, casirivimab and imdevimab, have been recently authorized by the USFDA. Nonetheless, their efficacy has not been demonstrated by multiple RCTs. In this review, we aim to dissect the various potential therapeutics used in children with COVID-19. We aspire to provide a comprehensive review of the available evidence and display the mechanisms of action and the pharmacokinetic properties of the studied therapeutics. Our review offers an efficient and practical guide for treating children with COVID-19.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Azitromicina/farmacologia , Criança , Dexametasona/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Ivermectina/farmacologia , Lopinavir/farmacologia , Oseltamivir/farmacologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
13.
J Clin Pharm Ther ; 46(5): 1459-1464, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34254323

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Tenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy. METHODS: Data were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data. RESULTS AND DISCUSSION: In women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics. WHAT IS NEW AND CONCLUSION: Tenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Tenofovir/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Adulto Jovem
14.
Eur Rev Med Pharmacol Sci ; 25(11): 4163-4173, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34156698

RESUMO

OBJECTIVE: As a beta-coronavirus, Coronavirus disease-2019 (COVID-19) has caused one of the most significant historical pandemics, as well as various health and medical challenges. Our purpose in this report is to collect, summarize, and articulate all essential information about antiviral drugs that may or may not be efficient for treating COVID-19. Clinical evidence about these drugs and their possible mechanisms of action are also discussed. MATERIALS AND METHODS: To conduct a comprehensive review, different keywords in various databases, including Web of Science, Scopus, Medline, PubMed, and Google Scholar, were searched relevant articles, especially the most recent ones, were selected and studied. These selected original research articles, review papers, systematic reviews, and even letters to the editors were then carefully reviewed for data collection. RESULTS: SARS-CoV-2 is the newest member of the coronavirus family, and there are still no promising therapies or particular antiviral compounds to fight it. After entering the body, SARS-CoV-2 penetrates the cells by attaching to specific lung cell receptors, called angiotensin-converting enzyme-2. Then, by employing cell division machinery, it replicates through a complex mechanism and spreads throughout the patient's body. Various antiviral drugs, including anti-influenza/HIV/HCV drugs, have been applied for treating COVID-19 patients. Due to the similarity of the structure and transcriptional mechanism of COVID-19 to a number of viruses, some of the listed drugs have been beneficial against SARS-CoV-2. However, the effectiveness of others is in an aura of ambiguity and doubt. CONCLUSIONS: Some of the antiviral medications listed and discussed in this article have been effective in the treatment of COVID-19 patients or preventing the virus from spreading further. However, other drugs have to be investigated to reach a reliable conclusion about their effectiveness or ineffectiveness.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Análise de Dados , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/metabolismo , Antivirais/farmacologia , COVID-19/metabolismo , Humanos , Lopinavir/metabolismo , Lopinavir/farmacologia , Lopinavir/uso terapêutico , SARS-CoV-2/metabolismo
15.
Chem Res Toxicol ; 34(4): 1150-1160, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33821626

RESUMO

Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC50 = 0.0514 µM), while lopinavir is a much weaker inhibitor (IC50 = 5.88 µM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a KI of 0.392 µM and a kinact of 0.119 min-1, illustrating the potential for CYP3A mediated drug-drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.


Assuntos
Antirretrovirais/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Sulfato de Desidroepiandrosterona/antagonistas & inibidores , Lopinavir/farmacologia , Ritonavir/farmacologia , Adulto , Antirretrovirais/química , Inibidores do Citocromo P-450 CYP3A/química , Sulfato de Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/metabolismo , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Recém-Nascido , Lopinavir/química , Conformação Molecular , Oxirredução , Ritonavir/química
16.
Eur J Clin Pharmacol ; 77(9): 1349-1356, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33754183

RESUMO

PURPOSE: S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. METHODS: In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. RESULTS: S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. CONCLUSIONS: Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.


Assuntos
Indutores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Lopinavir/farmacologia , Modelos Biológicos , Ritonavir/farmacologia , Varfarina/farmacologia , Fatores Etários , Área Sob a Curva , Teorema de Bayes , Citocromo P-450 CYP2C9/genética , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Fenótipo , Fatores Sexuais , Varfarina/administração & dosagem
17.
Viruses ; 13(2)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672333

RESUMO

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China at the end of 2019 causing a large global outbreak. As treatments are of the utmost importance, drug repurposing embodies a rich and rapid drug discovery landscape, where candidate drug compounds could be identified and optimized. To this end, we tested seven compounds for their ability to reduce replication of human coronavirus (HCoV)-229E, another member of the coronavirus family. Among these seven drugs tested, four of them, namely rapamycin, disulfiram, loperamide and valproic acid, were highly cytotoxic and did not warrant further testing. In contrast, we observed a reduction of the viral titer by 80% with resveratrol (50% effective concentration (EC50) = 4.6 µM) and lopinavir/ritonavir (EC50 = 8.8 µM) and by 60% with chloroquine (EC50 = 5 µM) with very limited cytotoxicity. Among these three drugs, resveratrol was less cytotoxic (cytotoxic concentration 50 (CC50) = 210 µM) than lopinavir/ritonavir (CC50 = 102 µM) and chloroquine (CC50 = 67 µM). Thus, among the seven drugs tested against HCoV-229E, resveratrol demonstrated the optimal antiviral response with low cytotoxicity with a selectivity index (SI) of 45.65. Similarly, among the three drugs with an anti-HCoV-229E activity, namely lopinavir/ritonavir, chloroquine and resveratrol, only the latter showed a reduction of the viral titer on SARS-CoV-2 with reduced cytotoxicity. This opens the door to further evaluation to fight Covid-19.


Assuntos
Antivirais/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Resveratrol/farmacologia , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Cloroquina/farmacologia , Coronavirus Humano 229E/fisiologia , Reposicionamento de Medicamentos , Humanos , Lopinavir/farmacologia , Masculino , SARS-CoV-2/fisiologia , Carga Viral
18.
Eur J Pharmacol ; 896: 173922, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33539819

RESUMO

The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , COVID-19 , Doxorrubicina/análogos & derivados , Lopinavir/farmacologia , SARS-CoV-2 , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Inibidores Enzimáticos/classificação , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Inibidores da Topoisomerase II/farmacologia
19.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33440983

RESUMO

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Assuntos
Antivirais/uso terapêutico , COVID-19/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Combinação de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/farmacologia , Indóis/uso terapêutico , Interferons/farmacologia , Interferons/uso terapêutico , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Nitrocompostos , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
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