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1.
Nihon Yakurigaku Zasshi ; 157(1): 27-30, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-34980807

RESUMO

The new coronavirus (SARS-CoV-2) spread throughout the world and caused a pandemic with COVID-19, an infection caused by SARS-CoV-2. Even today, an increase in the number of cases has also been observed in Japan. Since the drugs used in drug repositioning have already been tested for safety and pharmacokinetics in humans, it is possible to skip some development tests, and since the manufacturing method of the drug has already been established, it is possible to shorten the development period and reduce R&D costs. Therefore, the drug repositioning method is one of the methods that should be tried in order to achieve the initial control of a pandemic. In Japan, it has been announced that research and development using drug repositioning has been conducted to date. The following are some of the candidates that have already been identified as COVID-19 therapeutic agents in Japan and are expected to be identified in the future.


Assuntos
COVID-19 , Preparações Farmacêuticas , Antivirais/farmacologia , Antivirais/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Pandemias , SARS-CoV-2
2.
Nihon Yakurigaku Zasshi ; 157(1): 41-46, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-34980812

RESUMO

Although months have passed since WHO declared COVID-19 a global pandemic, only a limited number of clinically effective drugs are available, and the development of drugs to treat COVID-19 has become an urgent issue worldwide. The pace of new research on COVID-19 is extremely high and it is impossible to read every report. In order to tackle these problems, we leveraged our artificial intelligence (AI) system, Concept Encoder, to accelerate the process of drug repositioning. Concept Encoder is a patented AI system based on natural language processing technology and by deeply learning papers on COVID-19, the system identified a large group of genes implicated in COVID-19 pathogenesis. The AI system then generated a molecular linkage map for COVID-19, connecting the genes by learning the molecular relationship comprehensively. By thoroughly reviewing the resulting map and list of the genes with rankings, we found potential key players for disease progression and existing drugs that might improve COVID-19 survival. Here, we focus on potential targets and discuss the perspective of our approach.


Assuntos
COVID-19 , Reposicionamento de Medicamentos , Inteligência Artificial , Humanos , Pandemias , SARS-CoV-2
3.
Med Sci Monit ; 28: e935952, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34972812

RESUMO

On 4th November 2021, the first oral antiviral drug for COVID-19, molnupiravir (Lagevrio®), received full regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. Molnupiravir is an orally bioavailable antiviral drug for use at home when a SARS-CoV-2 test is positive. On 22nd December 2022, the FDA granted emergency use authorization (EUA) for the oral antiviral drug, nirmatrelvir/ritonavir (Paxlovid®) for adults and children with mild and moderate COVID-19 at increased risk of progression to severe COVID-19. These regulatory drug approvals come at a crucial time when new variants of concern of the SARS-CoV-2 virus are spreading rapidly. Although the FDA approved remdesivir (Veklury®) on 22nd October 2020 for use in adults and children for the treatment of COVID-19 requiring hospitalization, its use has been limited by the requirement for intravenous administration in a healthcare facility. The four FDA-approved therapeutic neutralizing monoclonal antibodies, imdevimab, bamlanivimab, etesevimab, and casirivimab are costly and also require medically-supervised intravenous administration. The availability of effective, low-cost oral antiviral drugs available in a community setting that can be used at an early stage of SARS-CoV-2 infection is now a priority in controlling COVID-19. An increasing number of repurposed antiviral drugs are currently under investigation or in the early stages of regulatory approval. This Editorial aims to present an update on the current status of orally bioavailable antiviral drug treatments for SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Citidina/análogos & derivados , Hidroxilaminas/uso terapêutico , Administração Oral , Anticorpos Monoclonais/uso terapêutico , Citidina/uso terapêutico , Aprovação de Drogas , Reposicionamento de Medicamentos/tendências , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Estados Unidos , United States Food and Drug Administration
4.
Methods Mol Biol ; 2390: 103-112, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731465

RESUMO

The development of vaccines for the treatment of COVID-19 is paving the way for new hope. Despite this, the risk of the virus mutating into a vaccine-resistant variant still persists. As a result, the demand of efficacious drugs to treat COVID-19 is still pertinent. To this end, scientists continue to identify and repurpose marketed drugs for this new disease. Many of these drugs are currently undergoing clinical trials and, so far, only one has been officially approved by FDA. Drug repurposing is a much faster route to the clinic than standard drug development of novel molecules, nevertheless in a pandemic this process is still not fast enough to halt the spread of the virus. Artificial intelligence has already played a large part in hastening the drug discovery process, not only by facilitating the selection of potential drug candidates but also in monitoring the pandemic and enabling faster diagnosis of patients. In this chapter, we focus on the impact and challenges that artificial intelligence has demonstrated thus far with respect to drug repurposing of therapeutics for the treatment of COVID-19.


Assuntos
Antivirais/uso terapêutico , Inteligência Artificial , COVID-19/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/efeitos adversos , COVID-19/diagnóstico , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Aprendizado de Máquina , Estrutura Molecular , SARS-CoV-2/patogenicidade , Relação Estrutura-Atividade
5.
F1000Res ; 102021.
Artigo em Inglês | MEDLINE | ID: mdl-34900223

RESUMO

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. As of March 1, 2021, Mexico had reached 2.11 million cases of COVID-19 and 189 thousand deaths; around 116 million cases and 2.57 million deaths are reported worldwide with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization and replication in the host cell. Methods: Rigid molecular docking was performed using receptor binding domain of the S1 subunit of S protein (RBD S1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved and prescribed by the Mexican Public Health System. The results were analyzed by docking score, frequency of the drug in receptor site and the types of interactions at the binding site residues. Results: About 40 drugs were identified as a potential inhibitor of RBD S1-ACE2 interaction. Within the top-ranked drugs, we identified ipratropium, formoterol and fexofenadine, which stands out as they are used as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.


Assuntos
COVID-19 , Reposicionamento de Medicamentos , Enzima de Conversão de Angiotensina 2 , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus
6.
Curr Microbiol ; 79(1): 12, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34905092

RESUMO

Pseudomonas aeruginosa is a ubiquitous bacterium found in hospitals and the surrounding environment. The ability of P. aeruginosa to form biofilms confers high-level resistance to antibiotics, and the persister cells formed in the presence of high antibacterial drug concentrations make P. aeruginosa-related infections more refractory. Further, there rarely is an effective antimicrobial alternative when biofilm- and persister cell-targeting treatment fails. Using a high-throughput screening assay, we previously identified fluoroquinolones sitafloxacin, prulifloxacin, and tosufloxacin as well as aminoglycoside sisomicin among FDA-approved drugs with significant bactericidal activity against P. aeruginosa. In addition, in our current study, these antibiotics exhibited an effective time- and dose-dependent eradication effects against the preformed biofilms of P. aeruginosa at the concentrations of 2-4 µM. These agents also exhibited bactericidal efficacy against CCCP-induced P. aeruginosa persister cells with the viable cell count decreased from 9.14 log10 CFU/mL to 6.15 (sitafloxacin), 7.59 (prulifloxacin), 4.27 (tosufloxacin), and 6.17 (sisomicin) log10 CFU/mL, respectively, following 4 h of treatment. Furthermore, sisomicin was also effective against conventional antibiotics induced persister cells in a time-dependent manner within 24 h. In addition, we confirmed the in vivo anti-biofilm efficacy of the identified antibiotics in a subcutaneous implantation biofilm-related infection model. Tosufloxacin exhibited the greatest in vivo bactericidal activity against P. aeruginosa biofilms with a reduction of 4.54 ΔLog10 CFU/mL compared to the vehicle group, followed by prulifloxacin, sitafloxacin, and sisomicin. Taken together, our results indicate that sitafloxacin, prulifloxacin, tosufloxacin, and sisomicin have great potential as alternatives for the treatment of refractory infections caused by P. aeruginosa biofilms and persister cells.


Assuntos
Anti-Infecciosos , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Biofilmes , Dioxolanos , Reposicionamento de Medicamentos , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana , Naftiridinas , Piperazinas , Sisomicina
7.
Curr Microbiol ; 79(1): 13, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34905109

RESUMO

Carbapenem-resistant Acinetobacter baumannii has been classified as a top priority for the development of new therapies due to its resistance to most antibiotics. Drug repurposing may be a fast and inexpensive strategy for treating this pathogen. This review aims to critically evaluate repurposed drugs for the treatment of infections caused by carbapenem-resistant A. baumannii, correlating their antimicrobial activity with data available for toxicity and side effects. Some drugs have been suggested as promising candidates for repurposing; however, in some cases, high toxicity and low plasma concentrations reduce applicability in clinical practice. The most favorable applicability is offered by fusidic acid and colistin, possibly combined with a third agent, promising to be well tolerated and achieving satisfactory plasma concentrations.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Colistina/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana
8.
Drug Discov Today Technol ; 39: 1-12, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34906319

RESUMO

Standing amidst the COVID-19 pandemic, we have faced major medical and economic crisis in recent times which remains to be an unresolved issue till date. Although the scientific community has made significant progress towards diagnosis and understanding the disease; however, effective therapeutics are still lacking. Several omics-based studies, especially proteomics and interactomics, have contributed significantly in terms of identifying biomarker panels that can potentially be used for the disease prognosis. This has also paved the way to identify the targets for drug repurposing as a therapeutic alternative. US Food and Drug Administration (FDA) has set in motion more than 500 drug development programs on an emergency basis, most of them are focusing on repurposed drugs. Remdesivir is one such success of a robust and quick drug repurposing approach. The advancements in omics-based technologies has allowed to explore altered host proteins, which were earlier restricted to only SARS-CoV-2 protein signatures. In this article, we have reviewed major contributions of proteomics and interactomics techniques towards identifying therapeutic targets for COVID-19. Furthermore, in-silico molecular docking approaches to streamline potential drug candidates are also discussed.


Assuntos
COVID-19 , Reposicionamento de Medicamentos , Antivirais/farmacologia , Humanos , Simulação de Acoplamento Molecular , Pandemias , Proteômica , SARS-CoV-2
9.
Nat Commun ; 12(1): 7327, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34916512

RESUMO

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.


Assuntos
Antivirais/química , COVID-19/tratamento farmacológico , Indóis/química , Software , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Indóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos
10.
Eur Rev Med Pharmacol Sci ; 25(23): 7565-7584, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34919258

RESUMO

OBJECTIVE: With the recent direction in drug repurposing, many approved drugs have been evaluated to assess their effect on the coronavirus or SARS-CoV-2 infection (COVID-19). Driving this path, chloroquine (CQ) has been used in the treatment of malaria and hydroxychloroquine (HCQ) in immunomodulatory and anti-thrombotic action, playing a leading role in initial management of the viral infection. MATERIALS AND METHODS: Literature search was done using Google Scholar, PubMed and Scopus database using keywords "chloroquine" "SARS-CoV-2" "COVID-19" "mechanism of action" and articles of interest were selected providing evidence of the possible role of CQ in viral infection. RESULTS: In a bid to understand how and if CQ and HCQ would exert their anti-viral property, mechanistic exegesis was done to review various proposed mechanisms of action. This revealed the inhibition of viral attachment and entry, inhibition of enveloped glycoprotein, inhibition of the development and proliferation of new viral particles as the way they perform their action. There is an interplay between iron metabolism and homeostasis with COVID-19 infection and viral reproduction. CONCLUSIONS: This study aims to show the functional role of CQ and HCQ, as well as to provide possible mechanistic insight on the role of iron on viral infection, iron starvation and its downstream cellular pathways involving hepcidin and proinflammatory cytokines. The overall aim of providing possible mode of action of CQ and HCQ in the management of COVID-19 infection is exhibited via its anti-viral, anti-inflammatory and anti-thrombotic activities.


Assuntos
COVID-19/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Ferro/metabolismo , COVID-19/metabolismo , Cloroquina/uso terapêutico , Reposicionamento de Medicamentos , Homeostase , Humanos , Hidroxicloroquina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Ligação Viral/efeitos dos fármacos
11.
Biomolecules ; 11(12)2021 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-34944476

RESUMO

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.


Assuntos
Anti-Inflamatórios/farmacologia , Inibidores de Caspase/farmacologia , Reposicionamento de Medicamentos/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anti-Inflamatórios/química , COVID-19/tratamento farmacológico , Caspase 1/metabolismo , Inibidores de Caspase/química , Humanos , Inflamação/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
12.
Molecules ; 26(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34946540

RESUMO

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics-generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from -4.6 ± 0.14 to -7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP-3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of -25.53 and -7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Acetatos/química , Acetatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Citidina Difosfato Colina/química , Citidina Difosfato Colina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Uridina/análogos & derivados , Uridina/química , Uridina/farmacologia
13.
Int J Mol Sci ; 22(24)2021 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-34948390

RESUMO

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify drug candidates that are able to block the entrance of the virus into human cells. By combining virtual screening with in vitro pseudovirus assays and antiviral assays in Human Lung Tissue (HLT) cells, we identify entrectinib as a potential antiviral drug.


Assuntos
Benzamidas/farmacologia , COVID-19/tratamento farmacológico , Indazóis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/farmacologia , Benzamidas/metabolismo , COVID-19/metabolismo , Linhagem Celular , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos/métodos , Humanos , Indazóis/metabolismo , Pulmão/patologia , Pulmão/virologia , Simulação de Acoplamento Molecular , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Células Vero , Ligação Viral/efeitos dos fármacos
14.
BMC Med Inform Decis Mak ; 21(Suppl 9): 304, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34789254

RESUMO

BACKGROUND: The historical data of rare disease is very scarce in reality, so how to perform drug repositioning for the rare disease is a great challenge. Most existing methods of drug repositioning for the rare disease usually neglect father-son information, so it is extremely difficult to predict drugs for the rare disease. METHOD: In this paper, we focus on father-son information mining for the rare disease. We propose GRU-Cooperation-Attention-Network (GCAN) to predict drugs for the rare disease. We construct two heterogeneous networks for information enhancement, one network contains the father-nodes of the rare disease and the other network contains the son-nodes information. To bridge two heterogeneous networks, we set a mapping to connect them. What's more, we use the biased random walk mechanism to collect the information smoothly from two heterogeneous networks, and employ a cooperation attention mechanism to enhance repositioning ability of the network. RESULT: Comparing with traditional methods, GCAN makes full use of father-son information. The experimental results on real drug data from hospitals show that GCAN outperforms state-of-the-art machine learning methods for drug repositioning. CONCLUSION: The performance of GCAN for drug repositioning is mainly limited by the insufficient scale and poor quality of the data. In future research work, we will focus on how to utilize more data such as drug molecule information and protein molecule information for the drug repositioning of the rare disease.


Assuntos
Reposicionamento de Medicamentos , Doenças Raras , Algoritmos , Biologia Computacional , Humanos , Proteínas , Doenças Raras/tratamento farmacológico
15.
Future Microbiol ; 16: 1341-1370, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34755538

RESUMO

Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Reposicionamento de Medicamentos/métodos , Humanos , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , Células Vero
16.
Curr Top Med Chem ; 21(16): 1429-1438, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34727849

RESUMO

As a part of the efforts to quickly develop pharmaceutical treatments for COVID-19 through repurposing existing drugs, some researchers around the world have combined the recently released crystal structure of SARS-CoV-2 Mpro in complex with a covalently bonded inhibitor with virtual screening procedures employing molecular docking approaches. In this context, protease inhibitors (PIs) clinically available and currently used to treat infectious diseases, particularly viral ones, are relevant sources of promising drug candidates to inhibit the SARS-CoV-2 Mpro, a key viral enzyme involved in crucial events during its life cycle. In the present perspective, we summarized the published studies showing the promising use of HIV and HCV PIs as potential repurposing drugs against the SARS-CoV-2 Mpro.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteínas M de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Sítios de Ligação , COVID-19/virologia , Proteínas M de Coronavírus/química , Proteínas M de Coronavírus/genética , Proteínas M de Coronavírus/metabolismo , Humanos , Cinética , Modelos Moleculares , Terapia de Alvo Molecular , Inibidores de Proteases/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2/enzimologia , SARS-CoV-2/genética , Termodinâmica
17.
Int J Mol Sci ; 22(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34769170

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.


Assuntos
Produtos Biológicos/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/efeitos dos fármacos , Desenho de Fármacos , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacos
18.
Mem Inst Oswaldo Cruz ; 116: e210207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34755820

RESUMO

BACKGROUND: Treatment of mycoses is often ineffective, usually prolonged, and has some side effects. These facts highlight the importance of discovering new molecules to treat fungal infections. OBJECTIVES: To search the Medicines for Malaria Venture COVID Box for drugs with antifungal activity. METHODS: Fourteen human pathogenic fungi were tested against the 160 drugs of this collection at 1.0 µM concentration. We evaluated the ability of the drugs to impair fungal growth, their fungicidal nature, and morphological changes caused to cells. FINDINGS: Thirty-four molecules (21.25%) presented antifungal activity. Seven are antifungal drugs and one is the agricultural fungicide cycloheximide. The other drugs with antifungal activity included antibiotics (n = 3), antimalarials (n = 4), antivirals (n = 2), antiparasitcs (n = 3), antitumor agents (n = 5), nervous system agents (n = 3), immunosuppressants (n = 3), antivomiting (n = 1), antiasthmatic (n = 1), and a genetic disorder agent (n = 1). Several of these drugs inhibited Histoplasma capsulatum and Paracoccidioides brasiliensis growth (15 and 20, respectively), while Fusarium solani was not affected by the drugs tested. Most drugs were fungistatic, but niclosamide presented fungicidal activity against the three dimorphic fungi tested. Cyclosporine affected morphology of Cryptococcus neoformans. MAIN CONCLUSIONS: These drugs represent new alternatives to the development of more accessible and effective therapies to treat human fungal infections.


Assuntos
COVID-19 , Cryptococcus neoformans , Malária , Preparações Farmacêuticas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Malária/tratamento farmacológico , Testes de Sensibilidade Microbiana , SARS-CoV-2
19.
Sci Rep ; 11(1): 21872, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750486

RESUMO

Severe acute respiratory syndrome (SARS) is a highly contagious viral respiratory illness. This illness is spurred on by a coronavirus known as SARS-associated coronavirus (SARS-CoV). SARS was first detected in Asia in late February 2003. The genome of this virus is very similar to the SARS-CoV-2. Therefore, the study of SARS-CoV disease and the identification of effective drugs to treat this disease can be new clues for the treatment of SARS-Cov-2. This study aimed to discover novel potential drugs for SARS-CoV disease in order to treating SARS-Cov-2 disease based on a novel systems biology approach. To this end, gene co-expression network analysis was applied. First, the gene co-expression network was reconstructed for 1441 genes, and then two gene modules were discovered as significant modules. Next, a list of miRNAs and transcription factors that target gene co-expression modules' genes were gathered from the valid databases, and two sub-networks formed of transcription factors and miRNAs were established. Afterward, the list of the drugs targeting obtained sub-networks' genes was retrieved from the DGIDb database, and two drug-gene and drug-TF interaction networks were reconstructed. Finally, after conducting different network analyses, we proposed five drugs, including FLUOROURACIL, CISPLATIN, SIROLIMUS, CYCLOPHOSPHAMIDE, and METHYLDOPA, as candidate drugs for SARS-CoV-2 coronavirus treatment. Moreover, ten miRNAs including miR-193b, miR-192, miR-215, miR-34a, miR-16, miR-16, miR-92a, miR-30a, miR-7, and miR-26b were found to be significant miRNAs in treating SARS-CoV-2 coronavirus.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/virologia , Reposicionamento de Medicamentos , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica , SARS-CoV-2 , Biologia Computacional , Redes Reguladoras de Genes , Genes Virais , Técnicas Genéticas , Humanos , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Biologia de Sistemas , Fatores de Transcrição
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