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2.
Int J Mol Sci ; 23(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35806297

RESUMO

Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure-activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers' length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.


Assuntos
Citocromo P-450 CYP3A , Ritonavir , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Heme , Piridinas , Ritonavir/química , Ritonavir/farmacologia
3.
Ned Tijdschr Geneeskd ; 1662022 05 31.
Artigo em Holandês | MEDLINE | ID: mdl-35899731

RESUMO

Certain drugs inherently have unfavourable pharmacokinetic properties; for example, they are poorly absorbed or broken down too quickly in the liver. In some cases, the addition of a pharmacokinetic excipient, thus deliberately causing an interaction, may offer a solution. To date, this concept has been most widely applied in HIV treatment where addition of the CYP3A inhibitors ritonavir and cobicistat greatly increases plasma levels of other HIV medications. For the same reason, ritonavir has been added to the new oral antiviral drug against the SARS CoV-2 virus, nirmatrelvir. In addition to a better and/or longer effect, theoretically lower doses can also be used, resulting in cost savings. Deliberately inducing a pharmacokinetic interaction is not without risk: after all, interactions with other CYP3A substrates can also occur. Nevertheless, we believe that with good interaction management, CYP3A inhibitors can be used safely with benefits for patients and society.


Assuntos
COVID-19 , Infecções por HIV , COVID-19/tratamento farmacológico , Citocromo P-450 CYP3A/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Humanos , Ritonavir/farmacologia , Ritonavir/uso terapêutico
4.
Cancer Chemother Pharmacol ; 90(1): 71-82, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35799067

RESUMO

PURPOSE: Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1). METHODS: Fifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling. RESULTS: A pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67-1.33) and 0.46 (95%CI: 0.34-0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122-724). CONCLUSION: The developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.


Assuntos
Paclitaxel , Ritonavir , Administração Oral , Disponibilidade Biológica , Composição de Medicamentos , Humanos , Ritonavir/farmacologia , Trombospondina 1
5.
Biomed Pharmacother ; 150: 113077, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35658217

RESUMO

77% of Romanians infected with HIV receive antiretroviral therapy, with the challenge of maintaining long-term therapeutic success (the viral load becoming/remaining undetectable). The main purpose of this study was to provide comparative analysis of the long-term virological response to therapeutic regimens containing pharmacokinetically enhanced darunavir (DRV) with ritonavir (RTV) or cobicistat (COBI). The second aim was to evaluate the viral resistance profile to therapy, by number/type/frequency of viral mutations. This retrospective study was conducted on 462 patients infected with subtype F HIV-1, registered at the "Matei Bals" National Institute of Infectious Diseases, between 2018 and 2021: 384 patients received (among other ARV) DRV 600 mg, enhanced with RTV 100 mg (twice daily) and 78 patients received DRV 800 mg boosted with COBI 150 mg (once daily). The virological response was measured by determining the viral load (HIV-1 RNA copies/mL), while the incidence of viral resistance to therapy was assessed by genotyping tests. Comparing the patients with undetectable viremia, from the 1st visit to the 3rd one, the outcomes showed that at the last visit, 84.6% subjects in the DRV/c group achieved virological efficiency over those from DRV/r group (76.8%). The differences observed between this time points are statistically significant p < 0.05. DRV/c administered in combination with other ARV, in subtype F HIV-1 infected patients, proved to be more virologically effective, maintaining a favorable long-time result. When comparing the outcomes of the two groups, a statistically significant difference of p < 0.05 was obtained. 32 patients (27 from DRV/r group and 5 from DRV/c group) were evaluated with persistent HIV-1 ARN plasma load > 1000 copies/mL, during all 3 clinical visits. They formed a research sub-group evaluated in terms of resistance to therapy and were reported as virological failures. 28.12% of the sub-group with persistent HIV-1 RNA > 1000 copies/mL were from the DRV/r group and only 3.12% from the DRV/c group. Drug mutations (DRM) involved in antiretroviral resistance/sensitivity occurred both in the protease gene, and in the reverse transcriptase gene, with the involved ARV classes being protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors. 16 different types of mutations were evaluated in the PR gene and 20 mutations were evaluated in RT gene.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores da Protease de HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Cobicistat/farmacologia , Cobicistat/uso terapêutico , Darunavir/efeitos adversos , Darunavir/uso terapêutico , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , RNA , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/farmacologia , Romênia , Carga Viral
6.
Viruses ; 14(5)2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35632843

RESUMO

Paxlovid is a promising, orally bioavailable novel drug for SARS-CoV-2 with excellent safety profiles. Our main goal here is to explore the pharmacometric features of this new antiviral. To provide a detailed assessment of Paxlovid, we propose a hybrid multiscale mathematical approach. We demonstrate that the results of the present in silico evaluation match the clinical expectations remarkably well: on the one hand, our computations successfully replicate the outcome of an actual in vitro experiment; on the other hand, we verify both the sufficiency and the necessity of Paxlovid's two main components (nirmatrelvir and ritonavir) for a simplified in vivo case. Moreover, in the simulated context of our computational framework, we visualize the importance of early interventions and identify the time window where a unit-length delay causes the highest level of tissue damage. Finally, the results' sensitivity to the diffusion coefficient of the virus is explored in detail.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Combinação de Medicamentos , Humanos , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir/farmacologia
7.
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
8.
Antimicrob Agents Chemother ; 66(6): e0013622, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35583344

RESUMO

Ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG) are affected by induction of metabolizing enzymes and efflux transporters caused by rifampicin (RIF). This complicates the treatment of people living with HIV (PLWH) diagnosed with tuberculosis. Recent data showed that doubling DRV/r dose did not compensate for this effect, and hepatic safety was unsatisfactory. We aimed to evaluate the pharmacokinetics of DRV, ritonavir (RTV), and DTG in the presence and absence of RIF in peripheral blood mononuclear cells (PBMCs). PLWH were enrolled in a dose-escalation crossover study with 6 treatment periods of 7 days. Participants started with DRV/r 800/100 mg once daily (QD), RIF and DTG were added before the RTV dose was doubled, and then they received DRV/r 800/100 twice daily (BD) and then 1,600/200 QD or vice versa. Finally, RIF was withdrawn. Plasma and intra-PBMC drug concentrations were measured through validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Seventeen participants were enrolled but only 4 completed all study phases due to high incidence of liver toxicity. Intra-PBMC DRV trough serum concentration (Ctrough) after the addition of RIF dropped from a median (interquartile range [IQR]) starting value of 261 ng/mL (158 to 577) to 112 ng/mL (18 to 820) and 31 ng/mL (12 to 331) for 800/100 BD and 1,600/200 QD DRV/r doses, respectively. The DRV intra-PBMC/plasma ratio increased significantly (P = 0.003). DTG and RIF intra-PBMC concentrations were in accordance with previous reports in the absence of RIF or DRV/r. This study showed a differential impact of enzyme and/or transporter induction on DRV/r concentrations in plasma and PBMCs, highlighting the usefulness of studying intra-PBMC pharmacokinetics with drug-drug interactions. (This study has been registered at ClinicalTrials.gov under registration no. NCT03892161.).


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores da Protease de HIV , Fármacos Anti-HIV/farmacocinética , Cromatografia Líquida , Estudos Cross-Over , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Compostos Heterocíclicos com 3 Anéis , Humanos , Leucócitos Mononucleares , Oxazinas , Piperazinas , Piridonas , Rifampina/farmacocinética , Rifampina/uso terapêutico , Ritonavir/farmacologia , Espectrometria de Massas em Tandem
9.
Drugs ; 82(5): 585-591, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35305258

RESUMO

Nirmatrelvir plus ritonavir (Paxlovid™; Pfizer) is a co-packaged combination of nirmatrelvir and ritonavir tablets, intended for co-administration and developed for the treatment and post-exposure prophylaxis of coronavirus disease 2019 (COVID-19). Nirmatrelvir is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease, while ritonavir is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor and CYP3A inhibitor. Nirmatrelvir plus ritonavir received its first conditional authorization in December 2021 in the United Kingdom, for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19. In January 2022, nirmatrelvir plus ritonavir received authorization in the EU for use in the same indication. Nirmatrelvir plus ritonavir is authorized for emergency use in the USA. This article summarizes the milestones in the development of nirmatrelvir plus ritonavir leading to its first authorizations and approval for the treatment of COVID-19.


Assuntos
COVID-19 , Ritonavir , Adulto , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2
10.
Dtsch Arztebl Int ; 119(15): 263-269, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35302484

RESUMO

BACKGROUND: Five-day oral therapies against early COVID-19 infection have recently been conditionally approved in Europe. In the drug combination nirmatrelvir + ritonavir (nirmatrelvir/r), the active agent, nirmatrelvir, is made bioavailable in clinically adequate amounts by the additional administration of a potent inhibitor of its first-pass metabolism by way of cytochrome P450 [CYP] 3A in the gut and liver. In view of the central role of CYP3A in the clearance of many different kinds of drugs, and the fact that many patients with COVID-19 are taking multiple drugs to treat other conditions, it is important to assess the potential for drug interactions when nirmatrelvir/r is given, and to minimize the risks associated with such interactions. METHODS: We defined the interaction profile of ritonavir on the basis of information derived from two databases (Medline, GoogleScholar), three standard electronic texts on drug interactions, and manufacturer-supplied drug information. We compiled a list of drugs and their potentially relevant interactions, developed a risk min - imization algorithm, and applied it to the substances in question. We also compiled a list of commonly prescribed drugs for which there is no risk of interaction with nirmatrelvir/r. RESULTS: Out of 190 drugs and drug combinations, 57 do not need any special measures when given in combination with brief, low-dose ritonavir treatment, while 15 require dose modification or a therapeutic alternative, 8 can be temporarily discontinued, 9 contraindicate ritonavir use, and 102 should preferably be combined with a different treatment. CONCLUSION: We have proposed measures that are simple to carry out for the main types of drug that can interact with ritonavir. These measures can be implemented under quarantine conditions before starting a 5-day treatment with nirmatrelvir/r.


Assuntos
COVID-19 , Citocromo P-450 CYP3A , Interações Medicamentosas , Humanos , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir/farmacologia , Ritonavir/uso terapêutico
11.
Nature ; 601(7894): 496, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35064230

Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Desenvolvimento de Medicamentos/tendências , Farmacorresistência Viral , Pesquisadores , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Oral , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/provisão & distribuição , COVID-19/mortalidade , COVID-19/prevenção & controle , Vacinas contra COVID-19/provisão & distribuição , Citidina/administração & dosagem , Citidina/análogos & derivados , Citidina/farmacologia , Citidina/uso terapêutico , Aprovação de Drogas , Combinação de Medicamentos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Quimioterapia Combinada , Hospitalização/estatística & dados numéricos , Humanos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Lactamas/administração & dosagem , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/administração & dosagem , Leucina/farmacologia , Leucina/uso terapêutico , Adesão à Medicação , Terapia de Alvo Molecular , Mutagênese , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/administração & dosagem , Prolina/farmacologia , Prolina/uso terapêutico , Parcerias Público-Privadas/economia , Ritonavir/administração & dosagem , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/enzimologia , SARS-CoV-2/genética
12.
Sci Rep ; 12(1): 1374, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082353

RESUMO

Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among HIV-1 B-clade. There is limited data on Gag mutations and their covariation with mutations in protease among HIV-1 non-B-clades at PI/r-based treatment failure. Thus, we characterized Gag mutations present in isolates from HIV-1 infected individuals treated with a PI/r-regimen (n = 143) and compared them with those obtained from individuals not treated with PI/r (ART-naïve [n = 101] or reverse transcriptase inhibitors (RTI) treated [n = 118]). The most frequent HIV-1 subtypes were CRF02_AG (54.69%), A (13.53%), D (6.35%) and G (4.69%). Eighteen Gag mutations showed a significantly higher prevalence in PI/r-treated isolates compared to ART-naïve (p < 0.05): Group 1 (prevalence < 1% in drug-naïve): L449F, D480N, L483Q, Y484P, T487V; group 2 (prevalence 1-5% in drug-naïve): S462L, I479G, I479K, D480E; group 3 (prevalence ≥ 5% in drug-naïve): P453L, E460A, R464G, S465F, V467E, Q474P, I479R, E482G, T487A. Five Gag mutations (L449F, P453L, D480E, S465F, Y484P) positively correlated (Phi ≥ 0.2, p < 0.05) with protease-resistance mutations. At PI/r-failure, no significant difference was observed between patients with and without these associated Gag mutations in term of viremia or CD4 count. This analysis suggests that some Gag mutations show an increased frequency in patients failing PIs among HIV-1 non-B clades.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/classificação , HIV-1/genética , Mutação , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Adulto , Contagem de Linfócito CD4 , Camarões/epidemiologia , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/virologia , Protease de HIV/genética , Inibidores da Protease de HIV/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Filogenia , Prevalência , Inibidores da Transcriptase Reversa/farmacologia , Ritonavir/farmacologia , Falha de Tratamento
14.
Eur J Clin Pharmacol ; 78(5): 733-753, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35088108

RESUMO

PURPOSE: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). METHOD: Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. RESULTS: Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. CONCLUSION: In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.


Assuntos
COVID-19 , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Dexametasona/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , Ivermectina/uso terapêutico , Lopinavir/efeitos adversos , Reprodutibilidade dos Testes , Ritonavir/farmacologia , SARS-CoV-2
15.
Mol Inform ; 41(2): e2100062, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34529322

RESUMO

In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS-CoV-2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top-100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS-CoV-2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration-dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.


Assuntos
Antivirais , Reposicionamento de Medicamentos , Drogas em Investigação/farmacologia , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Cefotiam/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Ritonavir/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores
16.
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
17.
J Biomol Struct Dyn ; 40(4): 1597-1606, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33030105

RESUMO

The rapid emergence of COVID-19 pandemics has posed humans particularly vulnerable to the novel SARS-CoV-2 virus. Since de novo drug discovery is both expensive and time-consuming, drug repurposing approaches are believed to be of particular help. The SARS-CoV-2 spike (S) protein is known to attach human angiotensin-converting enzyme-2 (hACE2) through its receptor-binding domain (RBD). We screened 1930 FDA-approved ligands for the selection of optimal ones blocking this interaction. Virtual screening predicted top 25 ligands docking to any of the reported binding sites. After exclusion of those ligands which were unsuitable for systemic use, the remaining 69 RBD-ligand complexes were screened based on the masking capacity of the amino acid residues engaged in RBD-hACE2 interaction, excluding 47 RBD-ligand complexes. A short molecular dynamics (MD) simulation analysis identified 11 globally stable complexes with the lowest RMSD (root-mean-square deviation). Next, a moderately long MD analysis revealed those six RBD-ligand complexes with the lowest RMSD variation, as a measure of global stability. Finally, a long MD analysis revealed two select candidate ligands, including ritonavir and naloxegol, highly stabilizing those key residues engaged in RBD-hACE2 interaction. A similar MD analysis of a few antiviral drugs which are under clinical trials or approved for COVID-19 treatment showed them inferior to both select ligands in terms of stabilizing the RBD globally and locally at binding sites. Because of the crucial role of the S protein in virus virulence, our results highly propose ritonavir and naloxegol as the potentially helpful therapeutics against COVID-19, mandating appropriate clinical trials.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Simulação de Dinâmica Molecular , COVID-19/tratamento farmacológico , Humanos , Morfinanos , Polietilenoglicóis , Ligação Proteica , Ritonavir/farmacologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
18.
Anticancer Res ; 41(12): 5987-5996, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34848452

RESUMO

BACKGROUND/AIM: Simultaneous inhibition of histone deacetylase and proteasomes induces endoplasmic reticulum (ER) stress efficiently. RTS-V5 is the first dual histone deacetylase-proteasome inhibitor, and we anticipated that combining it with the cytochrome P450 family 3 subfamily A member 4 inhibitor ritonavir would enhance its activity in bladder cancer cells. MATERIALS AND METHODS: Using bladder cancer cells (human T-24, J-82, murine MBT-2), we evaluated the ability and mechanism by which the combination of RTS-V5 and ritonavir induced ER stress and killed cancer cells. RESULTS: The combination of RTS-V5 and ritonavir triggered robust apoptosis and inhibited bladder cancer growth effectively in vitro and in vivo. It caused ubiquitinated protein accumulation and induced ER stress synergistically. The combination inhibited the mammalian target of rapamycin pathway by increasing the expression of AMP-activated protein kinase. We also found that the combination caused histone and tubulin hyperacetylation. CONCLUSION: Ritonavir enhances the ability of RTS-V5 to cause ER stress in bladder cancer cells.


Assuntos
Antineoplásicos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteassoma/farmacologia , Ritonavir/farmacologia , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Histonas/metabolismo , Humanos , Camundongos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária , Ensaios Antitumorais Modelo de Xenoenxerto
20.
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
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