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1.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34413211

RESUMO

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.


Assuntos
Antivirais/farmacologia , Fatores Imunológicos/farmacologia , Lactoferrina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Células Epiteliais , Heparitina Sulfato/antagonistas & inibidores , Heparitina Sulfato/imunologia , Heparitina Sulfato/metabolismo , Hepatócitos , Ensaios de Triagem em Larga Escala , Humanos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Células Vero
2.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445667

RESUMO

Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.


Assuntos
Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/fisiopatologia , Animais , Biologia Computacional/métodos , Biologia Computacional/tendências , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , Neurônios Motores/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445773

RESUMO

Inadequate vessel maintenance or growth causes ischemia in diseases such as myocardial infarction, stroke, and neurodegenerative disorders. Therefore, developing an effective strategy to salvage ischemic tissues using a novel compound is urgent. Drug repurposing has become a widely used method that can make drug discovery more efficient and less expensive. Additionally, computational virtual screening tools make drug discovery faster and more accurate. This study found a novel drug candidate for pro-angiogenesis by in silico virtual screening. Using Gene Expression Omnibus (GEO) microarray datasets related to angiogenesis studies, differentially expressed genes were identified and characteristic direction signatures extracted from GEO2EnrichR were used as input data on L1000CDS2 to screen pro-angiogenic molecules. After a thorough review of the candidates, a list of compounds structurally similar to TWS-119 was generated using ChemMine Tools and its clustering toolbox. ChemMine Tools and ChemminR structural similarity search tools for small-molecule analysis and clustering were used for second screening. A molecular docking simulation was conducted using AutoDock v.4 to evaluate the physicochemical effect of secondary-screened chemicals. A cell viability or toxicity test was performed to determine the proper dose of the final candidate, ellipticine. As a result, we found ellipticine, which has pro-angiogenic effects, using virtual computational methods. The noncytotoxic concentration of ellipticine was 156.25 nM. The phosphorylation of glycogen synthase kinase-3ß was decreased, whereas the ß-catenin expression was increased in human endothelial cells treated with ellipticine. We concluded that ellipticine at sublethal dosage could be successfully repositioned as a pro-angiogenic substance by in silico virtual screening.


Assuntos
Elipticinas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Neovascularização Patológica/metabolismo , Ligação Proteica/efeitos dos fármacos , beta Catenina/metabolismo
4.
DNA Repair (Amst) ; 106: 103180, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298488

RESUMO

Since the early stages of the pandemic, hydroxychloroquine (HCQ), a widely used drug with good safety profile in clinic, has come to the forefront of research on drug repurposing for COVID-19 treatment/prevention. Despite the decades-long use of HCQ in the treatment of diseases, such as malaria and autoimmune disorders, the exact mechanisms of action of this drug are only beginning to be understood. To date, no data are available on the genotoxic potential of HCQ in vitro or in vivo. The present study is the first investigation of the DNA damaging- and mutagenic effects of HCQ in mammalian cells in vitro, at concentrations that are comparable to clinically achievable doses in patient populations. We demonstrate significant induction of a representative oxidative DNA damage (8-oxodG) in primary mouse embryonic fibroblasts (MEFs) treated with HCQ at 5 and 25 µM concentrations (P = 0.020 and P = 0.029, respectively), as determined by enzyme-linked immunosorbent assay. Furthermore, we show significant mutagenicity of HCQ, manifest as 2.2- and 1.8-fold increases in relative cII mutant frequency in primary and spontaneously immortalized Big Blue® MEFs, respectively, treated with 25 µM dose of this drug (P = 0.005 and P = 0.012, respectively). The observed genotoxic effects of HCQ in vitro, achievable at clinically relevant doses, are novel and important, and may have significant implications for safety monitoring in patient populations. Given the substantial number of the world's population receiving HCQ for the treatment of various chronic diseases or in the context of clinical trials for COVID-19, our findings warrant further investigations into the biological consequences of therapeutic/preventive use of this drug.


Assuntos
Hidroxicloroquina/farmacologia , Mutação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Fibroblastos/virologia , Mamíferos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Pandemias/prevenção & controle , SARS-CoV-2/efeitos dos fármacos
5.
PLoS One ; 16(7): e0255270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324563

RESUMO

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become the current health concern and threat to the entire world. Thus, the world needs the fast recognition of appropriate drugs to restrict the spread of this disease. The global effort started to identify the best drug compounds to treat COVID-19, but going through a series of clinical trials and our lack of information about the details of the virus's performance has slowed down the time to reach this goal. In this work, we try to select the subset of human proteins as candidate sets that can bind to approved drugs. Our method is based on the information on human-virus protein interaction and their effect on the biological processes of the host cells. We also define some informative topological and statistical features for proteins in the protein-protein interaction network. We evaluate our selected sets with two groups of drugs. The first group contains the experimental unapproved treatments for COVID-19, and we show that from 17 drugs in this group, 15 drugs are approved by our selected sets. The second group contains the external clinical trials for COVID-19, and we show that 85% of drugs in this group, target at least one protein of our selected sets. We also study COVID-19 associated protein sets and identify proteins that are essential to disease pathology. For this analysis, we use DAVID tools to show and compare disease-associated genes that are contributed between the COVID-19 comorbidities. Our results for shared genes show significant enrichment for cardiovascular-related, hypertension, diabetes type 2, kidney-related and lung-related diseases. In the last part of this work, we recommend 56 potential effective drugs for further research and investigation for COVID-19 treatment. Materials and implementations are available at: https://github.com/MahnazHabibi/Drug-repurposing.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pandemias/prevenção & controle , Comorbidade , Aprovação de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos
6.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201401

RESUMO

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50-62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Indóis/química , Indóis/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Simulação por Computador , Reposicionamento de Medicamentos/métodos , Ergosterol/metabolismo , Aprendizado de Máquina , Simulação de Acoplamento Molecular/métodos
7.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205704

RESUMO

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Anti-Inflamatórios não Esteroides/metabolismo , Antivirais/química , Antivirais/farmacologia , Auranofina/química , Auranofina/farmacologia , Sítios de Ligação , COVID-19/complicações , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Bases de Dados de Compostos Químicos , Humanos , Indometacina/química , Indometacina/farmacologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação Proteica , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfimpirazona/química , Sulfimpirazona/farmacologia , Estados Unidos , United States Food and Drug Administration
8.
IEEE/ACM Trans Comput Biol Bioinform ; 18(4): 1290-1298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34081583

RESUMO

An outbreak of COVID-19 that began in late 2019 was caused by a novel coronavirus(SARS-CoV-2). It has become a global pandemic. As of June 9, 2020, it has infected nearly 7 million people and killed more than 400,000, but there is no specific drug. Therefore, there is an urgent need to find or develop more drugs to suppress the virus. Here, we propose a new nonlinear end-to-end model called LUNAR. It uses graph convolutional neural networks to automatically learn the neighborhood information of complex heterogeneous relational networks and combines the attention mechanism to reflect the importance of the sum of different types of neighborhood information to obtain the representation characteristics of each node. Finally, through the topology reconstruction process, the feature representations of drugs and targets are forcibly extracted to match the observed network as much as possible. Through this reconstruction process, we obtain the strength of the relationship between different nodes and predict drug candidates that may affect the treatment of COVID-19 based on the known targets of COVID-19. These selected candidate drugs can be used as a reference for experimental scientists and accelerate the speed of drug development. LUNAR can well integrate various topological structure information in heterogeneous networks, and skillfully combine attention mechanisms to reflect the importance of neighborhood information of different types of nodes, improving the interpretability of the model. The area under the curve(AUC) of the model is 0.949 and the accurate recall curve (AUPR) is 0.866 using 10-fold cross-validation. These two performance indexes show that the model has superior predictive performance. Besides, some of the drugs screened out by our model have appeared in some clinical studies to further illustrate the effectiveness of the model.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Redes Neurais de Computação , SARS-CoV-2/efeitos dos fármacos , COVID-19/epidemiologia , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/estatística & dados numéricos , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Humanos , Dinâmica não Linear , Pandemias
9.
Sci Rep ; 11(1): 12310, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112877

RESUMO

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , COVID-19/genética , Biologia Computacional/métodos , Humanos , SARS-CoV-2/fisiologia
10.
J Immunother Cancer ; 9(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34117116

RESUMO

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population.


Assuntos
COVID-19 , Reposicionamento de Medicamentos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Imunoterapia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/terapia , Comorbidade , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/estatística & dados numéricos , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Hospedeiro Imunocomprometido/fisiologia , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia/estatística & dados numéricos , Mortalidade , Pandemias , Prognóstico , Doenças Reumáticas/epidemiologia , SARS-CoV-2/fisiologia , Transplantados/estatística & dados numéricos
11.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063964

RESUMO

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antivirais/química , Antivirais/farmacologia , COVID-19/fisiopatologia , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Replicação Viral/efeitos dos fármacos
12.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064287

RESUMO

Therapeutics and vaccines against the COVID-19 pandemic need to be developed rapidly and efficiently, given its severity. To maximize the efficiency and productivity of drug development, the world has adopted disruptive technologies and approaches in various drug development areas. Telehealth, characterized by the heavy use of digital technologies; drug repositioning strategies, aided by computational breakthroughs; and data tracking tool hubs, enabling real-time information sharing, have received much attention. Moreover, drug developers have engaged in open innovation by establishing various types of collaborations, many of which have been carried out across nations and enterprises. Finally, regulatory agencies have attempted to operate on a more flexible review basis than before. Although such disruptive approaches have partly reshaped drug development practices, issues and challenges remain before the completion of this paradigm shift in conventional drug development practices for the post-pandemic era. In this review, we have highlighted the role of a collaborative community of experts in order to figure out how disruptive technologies can be fully integrated into the current drug development practices and improve drug development efficiency for the post-pandemic era.


Assuntos
COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Informática Médica/métodos , Telemedicina/métodos , Humanos , Pandemias , SARS-CoV-2
13.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067243

RESUMO

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , COVID-19/dietoterapia , Cafeína/farmacologia , Reposicionamento de Medicamentos/métodos , Músculo Liso/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , COVID-19/metabolismo , COVID-19/fisiopatologia , Humanos , Fatores Imunológicos/farmacologia , Simulação de Dinâmica Molecular , Músculo Liso/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo
14.
Nat Commun ; 12(1): 3309, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083527

RESUMO

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pandemias , SARS-CoV-2 , Animais , COVID-19/prevenção & controle , COVID-19/virologia , Linhagem Celular , Citidina/administração & dosagem , Citidina/análogos & derivados , Citidina/farmacologia , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/farmacologia , Mesocricetus , Nelfinavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
15.
PLoS One ; 16(5): e0251746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34010282

RESUMO

BACKGROUND: Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source. METHODS: Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998-2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations. RESULTS: Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11-3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31-1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01-4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41-2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25-4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00-1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51-4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02-2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02-1.19; 747 exposed cases) exposures were associated with MCM. CONCLUSIONS: Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.


Assuntos
Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Gravidez/efeitos dos fármacos , Adulto , Antivirais/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Nascido Vivo/epidemiologia , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Quebeque/epidemiologia , Fatores de Risco , SARS-CoV-2/efeitos dos fármacos
16.
BMJ ; 373: n1038, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975825

RESUMO

OBJECTIVE: To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents. DESIGN: Multinational network cohort study. SETTING: Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea. PARTICIPANTS: 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020. MAIN OUTCOME MEASURES: Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19. RESULTS: Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from <5 (<2%) patients in China to 2165 (85.1%) in Spain), azithromycin (from 15 (4.9%) in China to 1473 (57.9%) in Spain), combined lopinavir and ritonavir (from 156 (<2%) in the VA-OMOP US to 2,652 (34.9%) in South Korea and 1285 (50.5%) in Spain), and umifenovir (0% in the US, South Korea, and Spain and 238 (78.3%) in China). Use of adjunctive drugs varied greatly, with the five most used treatments being enoxaparin, fluoroquinolones, ceftriaxone, vitamin D, and corticosteroids. Hydroxychloroquine use increased rapidly from March to April 2020 but declined steeply in May to June and remained low for the rest of the year. The use of dexamethasone and corticosteroids increased steadily during 2020. CONCLUSIONS: Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. Antithrombotics, antibiotics, H2 receptor antagonists, and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of covid-19.


Assuntos
COVID-19/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Reposicionamento de Medicamentos/métodos , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Azitromicina/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Ceftriaxona/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Combinação de Medicamentos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Enoxaparina/uso terapêutico , Feminino , Fluoroquinolonas/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Lactente , Recém-Nascido , Pacientes Internados , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Segurança , Espanha/epidemiologia , Resultado do Tratamento , Estados Unidos/epidemiologia , Vitamina D/uso terapêutico , Adulto Jovem
17.
Pharmacol Rep ; 73(3): 926-938, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33970450

RESUMO

INTRODUCTION: Drug repurposing is the need of the hour considering the medical emergency caused by the COVID-19 pandemic. Recently, cytokine storm by the host immune system has been linked with high viral load, loss of lung function, acute respiratory distress syndrome (ARDS), multiple organ failure, and subsequent fatal outcome. OBJECTIVE: This study aimed to identify potential FDA approved drugs that can be repurposed for COVID-19 treatment using an in-silico analysis. METHODS: In this study, virtual screening of selected FDA approved drugs was performed by targeting the main protease (Mpro) of SARS-CoV-2 and the key molecules involved in the 'Cytokine storm' in COVID-19 patients. Based on our preliminary screening supported by extensive literature search, we selected FDA approved drugs to target the SARS-CoV-2 main protease (Mpro) and the key players of cytokine storm, TNF-α, IL-6, and IL-1ß. These compounds were examined based on systematic docking studies and further validated using a combination of molecular dynamics simulations and molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. RESULTS: Based on the findings, Rifampicin and Letermovir appeared as the most promising drug showing a very good binding affinity with the main protease of SARS-CoV-2 and TNF-α, IL-6, and IL-1ß. However, it is pertinent to mention here that our findings need further validation by in vitro analysis and clinical trials. CONCLUSION: This study provides an insight into the drug repurposing approach in which several FDA approved drugs were examined to inhibit COVID-19 infection by targeting the main protease of SARS-COV-2 and the cytokine storm.


Assuntos
Acetatos/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Quinazolinas/uso terapêutico , Rifampina/uso terapêutico , COVID-19/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/metabolismo , Reposicionamento de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2/efeitos dos fármacos , Proteases Virais/metabolismo
18.
Cell Rep ; 35(7): 109133, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33984267

RESUMO

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit Mpro do not synergize with remdesivir.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , COVID-19/virologia , Técnicas de Cultura de Células , Linhagem Celular , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Reposicionamento de Medicamentos/métodos , Sinergismo Farmacológico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Replicação Viral/efeitos dos fármacos
19.
Biomed Pharmacother ; 140: 111742, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34052565

RESUMO

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Reposicionamento de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular
20.
Sci Rep ; 11(1): 11049, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34040048

RESUMO

The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community's massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2/COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/fisiologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Terapia Combinada , Biologia Computacional , Sinergismo Farmacológico , Quimioterapia Combinada , GTP Fosfo-Hidrolases/uso terapêutico , Humanos , Bases de Conhecimento , Nelfinavir/uso terapêutico , Pandemias , Cloridrato de Raloxifeno/uso terapêutico
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