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1.
Virology ; 555: 10-18, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421743

RESUMO

Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2. We constructed three drug-target-pathways-disease networks to predict the targets and drugs interactions as well as important pathways involved in SARS-CoV-2. The results suggested that by using the combination of Lopinavir, Ritonavir along with Hydroxychloroquine and Vitamin C may turned out to be the effective line of treatment for SARS-CoV-2 as it shows the involvement of PARP-1, MAPK-8, EGFR, PRKCB, PTGS-2, and BCL-2. Gene ontology biological process analysis further confirmed multiple viral infection-related processes (P < 0.001), including viral life cycle, modulation by virus, C-C chemokine receptor activity, and platelet activation. KEGG pathway analysis involves multiple pathways (P < 0.05), including FoxO, GnRH, ErbB, Neurotrophin, Toll-like receptor, IL-17, TNF, Insulin, HIF-1, JAK-STAT, Estrogen, NF-kappa, Chemokine, VEGF, and Thyroid hormone signaling pathway in SARS-CoV-2. Docking study was carried out to predict the molecular mechanism Thus, the potential drug combinations could reduce viral infectivity, viral replication, and abnormal host inflammatory responses and may be useful for multi-target drugs against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Reposicionamento de Medicamentos , /efeitos dos fármacos , Antivirais/metabolismo , Antivirais/uso terapêutico , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Desenvolvimento de Medicamentos , Quimioterapia Combinada , Humanos , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Lopinavir/metabolismo , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Ritonavir/metabolismo , Ritonavir/farmacologia , Ritonavir/uso terapêutico , /fisiologia , Transdução de Sinais , Replicação Viral/efeitos dos fármacos
2.
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 , /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 , 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
3.
Int J Biol Macromol ; 168: 272-278, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33309661

RESUMO

SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.


Assuntos
Antivirais/farmacologia , Exorribonucleases/antagonistas & inibidores , Ritonavir/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Antivirais/administração & dosagem , Antivirais/química , Domínio Catalítico , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Exorribonucleases/química , Exorribonucleases/genética , Genoma Viral/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Pandemias , Ritonavir/administração & dosagem , Ritonavir/química , /fisiologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
4.
Sci Rep ; 10(1): 16986, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046764

RESUMO

We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein-ligand complexes and suggest the possibilities of further drug optimisations.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos/métodos , Inibidores da Protease de HIV/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas não Estruturais Virais/metabolismo , Betacoronavirus/metabolismo , Sítios de Ligação/efeitos dos fármacos , Fenômenos Biofísicos , Domínio Catalítico/efeitos dos fármacos , Biologia Computacional , Darunavir/metabolismo , Darunavir/farmacologia , Inibidores da Protease de HIV/metabolismo , Humanos , Indinavir/metabolismo , Indinavir/farmacologia , Lopinavir/metabolismo , Lopinavir/farmacologia , Simulação de Dinâmica Molecular , Nelfinavir/metabolismo , Nelfinavir/farmacologia , Pandemias , Ritonavir/metabolismo , Ritonavir/farmacologia , Saquinavir/metabolismo , Saquinavir/farmacologia
5.
J Mol Graph Model ; 101: 107762, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33022569

RESUMO

Since the emergence of SARS-CoV2, to date, no effective antiviral drug has been approved to treat the disease, and no vaccine against SARS-CoV2 is available. Under this scenario, the combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has attracted attention since they have been previously employed against the SARS-CoV main proteinase (Mpro) and exhibited some signs of effectiveness. Recently, the 3D structure of SARS-CoV2 Mpro was constructed based on the monomeric SARS-CoV Mpro and employed to identify potential approved small inhibitors against SARS-CoV2 Mpro, allowing the selection of 15 drugs among 1903 approved drugs to be employed. In this study, we performed docking of these 15 approved drugs against the recently solved X-ray crystallography structure of SARS-CoV2 Mpro in the monomeric and dimeric states; the latter is the functional state that was determined in a biological context, and these were submitted to molecular dynamics (MD) simulations coupled with the molecular mechanics generalized Born surface area (MM/GBSA) approach to obtain insight into the inhibitory activity of these compounds. Similar studies were performed with lopinavir and ritonavir coupled to monomeric and dimeric SARS-CoV Mpro and SARS-CoV2 Mpro to compare the inhibitory differences. Our study provides the structural and energetic basis of the inhibitory properties of lopinavir and ritonavir on SARS-CoV Mpro and SARS-CoV2 Mpro, allowing us to identify two FDA-approved drugs that can be used against SARS-CoV2 Mpro. This study also demonstrated that drug discovery requires the dimeric state to obtain good results.


Assuntos
Antivirais/farmacologia , Cisteína Endopeptidases/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/química , Cisteína Endopeptidases/metabolismo , Lopinavir/química , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Análise de Componente Principal , Conformação Proteica , Multimerização Proteica , Ritonavir/química , Ritonavir/farmacologia , Proteínas não Estruturais Virais/metabolismo
6.
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
7.
Medicine (Baltimore) ; 99(39): e22352, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991450

RESUMO

BACKGROUND: Antiretroviral therapy for HIV in sub-Saharan Africa has transformed the highly infectious virus to a stable chronic condition, with the advent of Highly active antiretroviral therapy (HAART). The longterm effects of HAART on the oral health of children are understudied. OBJECTIVE: To compare the effect of lopinavir-ritonavir and lamivudine on oral health indicators (dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children from the ANRS 12174 trial. METHODS: This study used data collected in 2017 among children aged 5 to 7 years from the Ugandan site of the ANRS 12174 randomized trial (ClinicalTrials.gov no: NCT00640263) implemented between 2009 and 2012 in Mbale district, Eastern Uganda. The intervention was lopinavir-ritonavir or lamuvudine treatment to prevent vertical HIV-1 transmission. One hundred thirty-seven and 139 children were randomized to receive lopinavir-ritonavir or lamivudine treatment at day 7 postpartum to compare efficacy of prevention of vertical HIV-1 transmission. At follow up, the children underwent oral examination using the World Health Organization methods for field conditions. The oral health related quality of life was assessed using the early childhood oral health impact scale. Negative binomial and logistic regression were used for the analysis of data. MAIN OUTCOME MEASURES: Dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children. RESULTS: The prevalence of dental caries was 48% in the study sample: 49% in the lopinavir-ritonavir arm and 48% in the lamivudine treatment group. The corresponding mean decayed missing filled teeth and standard deviation was 1.7 (2.4) and 2.3 (3.7) The mean number (standard deviation) of erupted permanent teeth was 3.8 (3.7) and 4.6 (3.9) teeth in the lopinavir- and lamivudine group, respectively. The prevalence of reported impacts on oral health was 7% in the lopinavir-ritonavir and 18% in the lamivudine group. Gingivitis had a prevalence of 7% in the lopinavir-ritonavir and 14% lamivudine treatment group. The regression analysis revealed 70% less reported impacts on oral health in lopinavir-ritonavir group than the lamivudine treatment group with an incidence rate ratio of 0.3 (95% confidence interval: 0.1-0.9). CONCLUSIONS: HIV exposed uninfected infants in the lopinavir-ritonavir group reported less impacts on oral health than the lamivudine treatment group. Dental caries, gingivitis, and tooth eruption were not significantly affected by the treatment lopinavir-ritonavir or lamivudine. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT00640263.


Assuntos
Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Saúde Bucal/estatística & dados numéricos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Cárie Dentária/tratamento farmacológico , Cárie Dentária/epidemiologia , Quimioterapia Combinada , Feminino , Gengivite/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Masculino , Avaliação de Resultados em Cuidados de Saúde , Prevalência , Qualidade de Vida , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Erupção Dentária/efeitos dos fármacos , Uganda/epidemiologia
8.
Biomed Pharmacother ; 131: 110668, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32861965

RESUMO

Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia with an unusual outbreak in Wuhan, China, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is currently no licensed antiviral treatment available to prevent human CoV infection. The widespread clinical use and existing knowledge on antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine in the treatment of previous epidemic diseases, namely, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), may be helpful in the combat with novel SARS-CoV-2 infection. Recent clinical evidence didn't confirm the beneficial role of lopinavir/ritonavir and chloroquine/hydroxychloroquine for COVID-19 patients and their use was reassessed. We provide an overview of the current evidence into the mechanisms of action of these available drugs which are repurposed for treatment of the new virus. Available data identifies remdesivir as an adenosine analogue that can target the RNA-dependent RNA polymerase and block viral RNA synthesis. It has been a promising antiviral drug against a wide array of RNA viruses. 3CLpro is a major CoV protease that cleaves the large replicase polyproteins during viral replication and can be targeted by the protease inhibitor lopinavir/ritonavir but the clinical effects are controversial. Chloroquine/Hydroxychloroquine could impair the replication of SARSCoV-2 by multiple mechanisms and their immunomodulatory properties could ameliorate clinical manifestations that are mediated by immune reactions of the host although its beneficial effects are under question and need to be proven at the clinical level. Existing in vitro and in vivo evidence delineate the molecular mechanisms of these drugs in CoV-infected cells. Numerous studies demonstrated the ability of remdesivir to inhibit SARS-CoV-2 replication but future research would be needed to understand the exact mode of action of lopinavir/ritonavir and chloroquine/hydroxychloroquine in SARS-CoV-2 infected cells and to use this knowledge in the treatment of the current COVID-19.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Cloroquina/farmacologia , Infecções por Coronavirus/virologia , Combinação de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Lopinavir/farmacologia , Pandemias , Pneumonia Viral/virologia , Ritonavir/farmacologia
9.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32759267

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.


Assuntos
Antivirais/farmacologia , Sulfato de Atazanavir/farmacologia , Betacoronavirus/efeitos dos fármacos , Citocinas/metabolismo , Ritonavir/farmacologia , Animais , Sulfato de Atazanavir/química , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Morte Celular/efeitos dos fármacos , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Quimioterapia Combinada , Humanos , Inflamação/metabolismo , Inflamação/virologia , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Monócitos/virologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Inibidores de Proteases/farmacologia , Células Vero , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
10.
Artigo em Inglês | MEDLINE | ID: mdl-32641296

RESUMO

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 µg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.


Assuntos
Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Hidroxicloroquina/farmacocinética , Lopinavir/farmacocinética , Pneumonia Viral/tratamento farmacológico , Ritonavir/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/sangue , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hospitais Universitários , Humanos , Hidroxicloroquina/sangue , Hidroxicloroquina/farmacologia , Tempo de Internação/estatística & dados numéricos , Lopinavir/sangue , Lopinavir/farmacologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Retrospectivos , Ritonavir/sangue , Ritonavir/farmacologia , Índice de Gravidade de Doença , Análise de Sobrevida
12.
Expert Opin Investig Drugs ; 29(8): 793-796, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32475183

RESUMO

INTRODUCTION: Lopinavir in combination with ritonavir is approved for the treatment of HIV and has recently been subject to a clinical trial in severe COVID-19. AREAS COVERED: This evaluation is of LOTUS China (the Lopinavir Trial for Suppression of SARS-Cov-2 in China), which was a randomized trial in hospitalized subjects with COVID-9 in a respiratory sample and pneumonia. As, in severe COVID-19, lopinavir/ritonavir had no beneficial effects but increased gastrointestinal adverse effects, this combination should not be used at this stage of COVID-19. EXPERT OPINION: In my opinion, the rationale for undertaking a trial of lopinavir/ritonavir in COVID-19 was poor. The analysis of a modified intention to treat group analysis in LOTUS China may have introduced bias. After LOTUS China, there is probably no future for lopinavir in the treatment of severe COVID-19, but some clinical trials for prevention or in various stages of COVID-19 have recently started or are ongoing. The major limitation of these trials is that as lopinavir does not inhibit COVID-19, it is unlikely to prevent infection, reduce viral load, or reduce the severity. However, these trials may be worthwhile in finally determining whether lopinavir has any role in preventing or treating COVID-19.


Assuntos
Antivirais/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Lopinavir/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Ritonavir/administração & dosagem , Antivirais/farmacologia , Infecções por Coronavirus/virologia , Combinação de Medicamentos , Humanos , Lopinavir/farmacologia , Pandemias , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/farmacologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
13.
Biotechniques ; 69(2): 108-112, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32459144

RESUMO

The outbreak of viral pneumonia caused by the novel coronavirus SARS-CoV-2 that began in December 2019 caused high mortality. It has been suggested that the main protease (Mpro) of SARS-CoV-2 may be an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. Remdesivir, ritonavir and chloroquine have all been reported to play a role in suppressing SARS-CoV-2. Here, we applied a molecular docking method to study the binding stability of these drugs with SARS-CoV-2 Mpro. It appeared that the ligand-protein binding stability of the alliin and SARS-CoV-2 Mpro complex was better than others. The results suggested that alliin may serve as a good candidate as an inhibitor of SARS-CoV-2 Mpro. Therefore, the present research may provide some meaningful guidance for the prevention and treatment of SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Cisteína/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Antimaláricos/farmacologia , Betacoronavirus/enzimologia , Cloroquina/farmacologia , Cisteína/farmacologia , Cisteína Endopeptidases , Simulação de Acoplamento Molecular , Ritonavir/farmacologia
15.
Can J Cardiol ; 36(6): 948-951, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32299753

RESUMO

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.


Assuntos
Arritmias Cardíacas , Azitromicina/farmacologia , Infecções por Coronavirus , Hidroxicloroquina/farmacologia , Síndrome do QT Longo , Pandemias , Pneumonia Viral , Gestão de Riscos/métodos , Ritonavir/farmacologia , Antivirais/farmacologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/prevenção & controle , Betacoronavirus/isolamento & purificação , Canadá , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia
16.
Biochemistry ; 59(18): 1769-1779, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32293875

RESUMO

Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Lopinavir/química , Lopinavir/farmacologia , Pneumonia Viral/tratamento farmacológico , Ritonavir/química , Ritonavir/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Domínio Catalítico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Humanos , Lopinavir/uso terapêutico , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Ligação Proteica , Estrutura Terciária de Proteína , Ritonavir/uso terapêutico , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
17.
J Enzyme Inhib Med Chem ; 35(1): 629-638, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037904

RESUMO

Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.


Assuntos
Antifúngicos/farmacologia , Ácido Aspártico Proteases/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Macrófagos/efeitos dos fármacos , Phialophora/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Ácido Aspártico Proteases/metabolismo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Relação Dose-Resposta a Droga , Furanos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Lopinavir/síntese química , Lopinavir/química , Lopinavir/farmacologia , Macrófagos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Phialophora/enzimologia , Phialophora/crescimento & desenvolvimento , Ritonavir/síntese química , Ritonavir/química , Ritonavir/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
18.
Evid. actual. práct. ambul ; 23(2): e002057, 2020.
Artigo em Espanhol | LILACS | ID: biblio-1103663

RESUMO

La pandemia de COVID-19 está generando información epidemiológica y clínica en una escala sin precedentes para una enfermedad de reciente aparición. Aunque ya se han iniciado numerosos ensayos clínicos de fármacos antiguos y nuevos como potenciales antivirales específicos, la mayor parte de la información publicada hasta ahora carece de los controles básicos para la evaluación de la eficacia de un medicamento. Los medios de comunicación amplifican estos resultados preliminares y suman presión a los médicos asistenciales y a los decisores de políticas públicas. Este artículo revisa las pruebas disponibles sobre los cuatro tratamientos antivirales específicos más prometedores: hidroxicloroquina, lopinavir/ritonavir, remdesvir e interferones alfa y beta. Se comprueba en todos ellos que no hay demostración suficiente de eficacia como para recomendar su uso fuera de una investigación experimental adecuadamente controlada. En el uso individual de un medicamento no hay forma de saber si está beneficiando o perjudicando al paciente. Es erróneo asumir que la eventual curación se debe al fármaco y un mal desenlace debe atribuirse a la enfermedad. Sólo la comparación entre grupos de pacientes asignados al tratamiento experimental o a un control adecuado permite conocer la eficacia y seguridad de las intervenciones. El desafío es conciliar la urgencia de actuar con la generación de nuevos conocimientos.Aunque no resulta sencillo organizar ensayos clínicos en este contexto, las instituciones pueden sumarse a los proyectos en marcha a nivel nacional e internacional. El uso de estos fármacos debe considerarse experimental, por lo que es necesario obtener el consentimiento informado del paciente. (AU)


The COVID-19 pandemic is generating epidemiological and clinical information on an unprecedented scale for a newly emerging disease. Although numerous clinical trials of old and new drugs as potential specific antivirals have already been started, most of the information published so far lacks basic controls for evaluating drug efficacy. The media amplify these preliminary results and add pressure to doctors and policymakers. This article reviews the available evidence for the four most promising specific antiviral treatments: hydroxychloroquine, lopinavir / ritonavir, remdesvir, and alpha and beta interferons. The findings show that none of them has sufficient demonstration of efficacy to recommend its use outside ofthe adequately controlled experimental study. In the individual use of a drug there is no way of knowing if it is benefiting orharming the patient. It is wrong to assume that the eventual cure is due to the drug and a poor outcome must be attributed to the disease. Only the comparison between groups of patients assigned to the experimental treatment or to an adequate control can establish the efficacy and safety of the interventions. The challenge is to reconcile the urgency to act with the generation of new knowledge. Although it is not easy to organize clinical trials in this context, the institutions can join theongoing projects at the national and international levels. The use of these drugs should be considered experimental, so it is necessary to obtain the informed consent of the patient. (AU)


Assuntos
Humanos , Antivirais/farmacologia , Pneumonia Viral/tratamento farmacológico , Interferons/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Ritonavir/farmacologia , Lopinavir/farmacologia , Hidroxicloroquina/farmacologia , Antivirais/efeitos adversos , Resultado do Tratamento , Azitromicina/farmacologia , Medição de Risco , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Medicina Baseada em Evidências/tendências , Disseminação de Informação , Uso Off-Label , Comunicação em Saúde , Pandemias , Lopinavir/administração & dosagem , Lopinavir/efeitos adversos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Consentimento Livre e Esclarecido
19.
Anticancer Res ; 39(11): 5891-5901, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704813

RESUMO

BACKGROUND/AIM: Induction of endoplasmic reticulum (ER) stress is a novel approach to cancer treatment. This study investigated the ability of the clinically feasible combination of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir to induce ER stress killing urological cancer cells. MATERIALS AND METHODS: Renal cancer cells (769-P, 786-O) and bladder cancer cells (UMUC-3, T-24) were used to investigate the ability of the combination to induce ER stress and its mechanism of action. RESULTS: The combination inhibited the growth of both renal and bladder cancer cells synergistically by inducing ER stress. The combination-induced ER stress increased the expression of AMP-activated protein kinase and suppressed the mammalian target of rapamycin pathway. It also increased the expression of a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor and thereby sensitized the cancer cells to TRAIL. CONCLUSION: The combination of lopinavir and ritonavir acts against urological cancer cells by inducing ER stress synergistically.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Lopinavir/farmacologia , Ritonavir/farmacologia , Neoplasias Urológicas/tratamento farmacológico , Quimioterapia Combinada , Humanos , Células Tumorais Cultivadas , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/patologia
20.
Lancet HIV ; 6(11): e750-e759, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31601544

RESUMO

BACKGROUND: The decision about whether to switch to third-line antiretroviral therapy (ART) in patients with treatment failure on second-line therapy is difficult in settings with little access to genotypic resistance testing. In this study, we used a standardised algorithm including a wide range of adherence-enhancing interventions followed by a new viral load measurement to decide whether to switch to third-line therapy in this situation. The decision, made on the basis of effectiveness of the adherence reinforcement to drive viral resuppression, did not use genotypic resistance testing. METHODS: In this prospective cohort study, adults in four west African countries with treatment failure of a boosted protease inhibitor ART regimen were offered nine adherence reinforcement interventions, and followed up for 64 weeks. We measured viral load at week 12 and used the results to decide ART treatment at week 16: if successful resuppression (plasma HIV-1 RNA <400 copies per mL or had decreased by ≥2 log10 copies per mL compared with baseline), patients continued the same second-line regimen; otherwise they switched to a third-line regimen based on ritonavir-boosted darunavir and raltegravir. The primary endpoint was virological success at week 64 (plasma HIV-1 RNA <50 copies per mL). After study termination we did genotypic resistance testing on frozen plasma samples collected at baseline, and retrospectively determined the appropriateness of the week 16 decision on the basis of the baseline genotypic susceptibility score. FINDINGS: Between March 28, 2013, and May 11, 2015, of the 198 eligible participants, five died before week 16. Of the 193 remaining, 130 (67%) reached viral resuppression and continued with second-line ART, and 63 (33%) switched to third-line ART at week 16. Post-study genotypic resistance testing showed that the baseline genotypic susceptibility score was calculable in 166 patients, of whom 57 (34%) had a score less than 2. We retrospectively concluded that the week 16 decision was appropriate in 145 (75%) patients. At week 64, four patients (2%) were lost to follow-up, ten (5%) had died, and 101 (52%) had a viral load less than 50 copies per mL. INTERPRETATION: Poor adherence is the first problem to tackle in patients for whom second-line ART is failing when resistance tests are not routinely available and is effectively a manageable problem. Lack of access to genotypic resistance testing should not be an obstacle to the prescription of third-line ART in patients who do not achieve viral resuppression after adherence reinforcement. FUNDING: French Agency for Research on AIDS and Viral Hepatitis.


Assuntos
Darunavir/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Raltegravir Potássico/administração & dosagem , Ritonavir/administração & dosagem , Adulto , África Ocidental , Algoritmos , Tomada de Decisão Clínica , Darunavir/efeitos adversos , Darunavir/farmacologia , Quimioterapia Combinada/efeitos adversos , Feminino , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Prospectivos , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/farmacologia , Ritonavir/efeitos adversos , Ritonavir/farmacologia , Falha de Tratamento , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
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