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1.
Int J Immunopathol Pharmacol ; 34: 2058738420966078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33045858

RESUMO

Given the sharp spreading of COVID-19 pandemic all around the world, our attention was brought to consider that that many cationic drugs (i.e. those characterized by the presence, at physiological pH value, of one or more cationic groups, both primary, secondary, tertiary and guanidinic aminic groups) could have any effect in impairing SARS-CoV2 entry in the host cell. This could open to new therapeutic chances against COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Inibidores Enzimáticos/farmacologia , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Humanos , Pandemias , Pneumonia Viral/epidemiologia
2.
Pharm Res ; 37(11): 212, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025261

RESUMO

PURPOSE: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette-Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. METHODS: We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. RESULTS: Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. CONCLUSIONS: Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2.


Assuntos
Vacina BCG/administração & dosagem , Materiais Biomiméticos/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Reposicionamento de Medicamentos/métodos , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Bibliotecas de Moléculas Pequenas/administração & dosagem , Vacinas Virais/administração & dosagem , Vacina BCG/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Humanos , Imunidade Inata , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Biologia de Sistemas/métodos , Vacinas Virais/imunologia , Fluxo de Trabalho
3.
BMC Endocr Disord ; 20(1): 149, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993622

RESUMO

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. MAIN TEXT: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. CONCLUSION: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.


Assuntos
Anti-Inflamatórios/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Reposicionamento de Medicamentos/métodos , Sistema Endócrino , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Prognóstico
4.
Front Immunol ; 11: 2159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983179

RESUMO

The rapid spread, severity, and lack of specific treatment for COVID-19 resulted in hasty drug repurposing. Conceptually, trials of antivirals were well-accepted, but twentieth century antimalarials sparked an impassioned global debate. Notwithstanding, antiviral and immunomodulatory effects of aminoquinolines have been investigated in vitro, in vivo and in clinical trials for more than 30 years. We review the mechanisms of action of (hydroxy)chloroquine on immune cells and networks and discuss promises and pitfalls in the fight against SARS-CoV-2, the agent of the COVID-19 outbreak.


Assuntos
Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
5.
PLoS Negl Trop Dis ; 14(9): e0008353, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970675

RESUMO

Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 µM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.


Assuntos
Amebíase/tratamento farmacológico , Amebicidas/farmacologia , Reposicionamento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Acanthamoeba/efeitos dos fármacos , Balamuthia mandrillaris/efeitos dos fármacos , Bases de Dados de Produtos Farmacêuticos , Naegleria fowleri/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas
6.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
7.
Front Immunol ; 11: 2094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973818

RESUMO

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.


Assuntos
Betacoronavirus , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Butirofenonas/farmacologia , Butirofenonas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Infecções por Coronavirus/virologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Pandemias , Peptidil Dipeptidase A/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonia Viral/virologia , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
8.
OMICS ; 24(10): 568-580, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32757981

RESUMO

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.


Assuntos
Antimaláricos/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Antimaláricos/química , Antivirais/química , Betacoronavirus/química , Sítios de Ligação , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/efeitos dos fármacos , Doxiciclina/química , Doxiciclina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacos
9.
Front Immunol ; 11: 1664, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754161

RESUMO

The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.


Assuntos
Betacoronavirus/fisiologia , Simulação por Computador , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Interface Usuário-Computador , Internalização do Vírus/efeitos dos fármacos , Anti-Inflamatórios/uso terapêutico , Sítios de Ligação , Infecções por Coronavirus/virologia , Genoma Viral/genética , Humanos , Modelos Genéticos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Ligação Viral
10.
Life Sci ; 259: 118169, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738360

RESUMO

AIMS: The recent outbreak of pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led the world towards a global health emergency. Currently, no proper medicine or effective treatment strategies are available; therefore, repurposing of FDA approved drugs may play an important role in overcoming the situation. MATERIALS AND METHODS: The SARS-CoV-2 genome encodes for 2-O-methyltransferase (2'OMTase), which plays a key role in methylation of viral RNA for evading host immune system. In the present study, the protein sequence of 2'OMTase of SARS-CoV-2 was analyzed, and its structure was modeled by a comparative modeling approach and validated. The library of 3000 drugs was screened against the active site of 2'OMTase followed by re-docking analysis. The apo and ligand-bound 2'OMTase were further validated and analyzed by using molecular dynamics simulation. KEY FINDINGS: The modeled structure displayed the conserved characteristic fold of class I MTase family. The quality assessment analysis by SAVES server reveals that the modeled structure follows protein folding rules and of excellent quality. The docking analysis displayed that the active site of 2'OMTase accommodates an array of drugs, which includes alkaloids, antivirals, cardiac glycosides, anticancer, steroids, and other drugs. The redocking and MD simulation analysis of the best 5 FDA approved drugs reveals that these drugs form a stable conformation with the 2'OMTase. SIGNIFICANCE: The results suggested that these drugs may be used as potential inhibitors for 2'OMTase for combating the SARS-CoV-2 infection.


Assuntos
Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Metiltransferases/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/farmacologia , Biologia Computacional/métodos , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Metilação/efeitos dos fármacos , Metiltransferases/química , Metiltransferases/metabolismo , Metiltransferases/ultraestrutura , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/virologia , Homologia de Sequência de Aminoácidos
11.
Sci Rep ; 10(1): 13866, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807895

RESUMO

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


Assuntos
Betacoronavirus/efeitos dos fármacos , Biologia Computacional/métodos , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Betacoronavirus/química , Sítios de Ligação , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Simeprevir/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo
12.
Int J Mol Sci ; 21(17)2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32825444

RESUMO

At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug's safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.


Assuntos
Aciclovir/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Butiratos/química , Crisenos/química , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Aciclovir/farmacologia , Antivirais/farmacologia , Disponibilidade Biológica , Butiratos/farmacologia , Química Farmacêutica/métodos , Crisenos/farmacologia , Reposicionamento de Medicamentos/métodos , Humanos , Líquidos Iônicos/química , Pandemias , Solubilidade
13.
Cell Metab ; 32(2): 145-147, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32755604

RESUMO

The COVID-19 pandemic has driven unprecedented efforts to identify existing treatments that can be quickly and effectively repurposed to reduce morbidity and mortality. In this issue of Cell Metabolism, Zhang et al. (2020) report an association between statin use and improved outcomes in a large observational study of hospitalized COVID-19 patients. Given the widespread availability, low cost, and safety of statins, this promising result should be further investigated in randomized controlled trials.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Humanos , Estudos Observacionais como Assunto , Pandemias
14.
Chin J Integr Med ; 26(9): 663-669, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32740825

RESUMO

OBJECTIVE: To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening. METHODS: The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper. RESULTS: It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score. CONCLUSIONS: A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Medicamentos de Ervas Chinesas/farmacologia , Glicoproteínas/efeitos dos fármacos , Imageamento Tridimensional , Simulação de Acoplamento Molecular/métodos , Pneumonia Viral/tratamento farmacológico , China , Simulação por Computador , Infecções por Coronavirus/diagnóstico , Glicoproteínas/metabolismo , Humanos , Programas de Rastreamento/métodos , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/diagnóstico , Ligação Proteica , Estados Unidos , United States Food and Drug Administration
15.
PLoS Comput Biol ; 16(8): e1008098, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764756

RESUMO

Drug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson's disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.


Assuntos
Biologia Computacional/métodos , Reposicionamento de Medicamentos/métodos , Aprendizado de Máquina , Software , Algoritmos , Antiparkinsonianos , Hipoglicemiantes , Modelos Estatísticos
16.
J Med Internet Res ; 22(8): e21169, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32735546

RESUMO

BACKGROUND: Driven by the COVID-19 pandemic and the dire need to discover an antiviral drug, we explored the landscape of the SARS-CoV-2 biomedical publications to identify potential treatments. OBJECTIVE: The aims of this study are to identify off-label drugs that may have benefits for the coronavirus disease pandemic, present a novel ranking algorithm called CovidX to recommend existing drugs for potential repurposing, and validate the literature-based outcome with drug knowledge available in clinical trials. METHODS: To achieve such objectives, we applied natural language processing techniques to identify drugs and linked entities (eg, disease, gene, protein, chemical compounds). When such entities are linked, they form a map that can be further explored using network science tools. The CovidX algorithm was based upon a notion that we called "diversity." A diversity score for a given drug was calculated by measuring how "diverse" a drug is calculated using various biological entities (regardless of the cardinality of actual instances in each category). The algorithm validates the ranking and awards those drugs that are currently being investigated in open clinical trials. The rationale behind the open clinical trial is to provide a validating mechanism of the PubMed results. This ensures providing up to date evidence of the fast development of this disease. RESULTS: From the analyzed biomedical literature, the algorithm identified 30 possible drug candidates for repurposing, ranked them accordingly, and validated the ranking outcomes against evidence from clinical trials. The top 10 candidates according to our algorithm are hydroxychloroquine, azithromycin, chloroquine, ritonavir, losartan, remdesivir, favipiravir, methylprednisolone, rapamycin, and tilorone dihydrochloride. CONCLUSIONS: The ranking shows both consistency and promise in identifying drugs that can be repurposed. We believe, however, the full treatment to be a multifaceted, adjuvant approach where multiple drugs may need to be taken at the same time.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Pandemias
17.
Life Sci ; 259: 118275, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32818545

RESUMO

The recent outbreak of Coronavirus disease (COVID-19), first in Eastern Asia and then essentially across the world has been declared a pandemic by the WHO. COVID-19 is caused by a novel virus SARS-CoV2 (2019-nCoV), against which there is currently no vaccine available; and current antiviral therapies have failed, causing a very high mortality rate. Drug repurposing i.e. utilizing an approved drug for different indication, offers a time- and cost-efficient alternative for making new therapies available to patients. Although there are several reports presenting novel approaches to treat COVID-19, still an attentive review of previous scientific literature is essential to overcome their failure to exhibit efficacy. There is an urgent need to provide a comprehensive outlook toward utilizing drug repurposing as a tool for discovery of new therapies against COVID-19. In this article, we aim to provide a to-the-point review of current literature regarding efficacy of repurposed drugs against COVID-19 and other respiratory infections caused by coronaviruses. We have briefly discussed COVID-19 epidemiology, and then have discussed drug repurposing approaches and examples, specific to respiratory viruses. Limitations of utilization of repurposed drug molecules such as dosage regimen and associated challenges such as localized delivery in respiratory tract have also been discussed in detail.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Antivirais/uso terapêutico , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/virologia
19.
Int J Cardiol ; 318: 160-164, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32610153

RESUMO

The novel coronavirus disease, affecting ~9 million people in the past five months and causing >460,000 deaths worldwide, is completely new to mankind. More than 2,000 research projects registered at ClinTrials.gov are aiming at finding effective treatments for rapid transfer to clinical practice. Unfortunately, just few studies have a sufficiently valid design to provide reliable information for clinical practice.


Assuntos
Antivirais/farmacologia , Ensaios Clínicos como Assunto , Infecções por Coronavirus , Reposicionamento de Medicamentos/métodos , Pandemias , Pneumonia Viral , Terapias em Estudo/métodos , Betacoronavirus , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/organização & administração , Ensaios Clínicos como Assunto/normas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Humanos , Itália , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pesquisa , Projetos de Pesquisa
20.
Diabetes Metab Syndr ; 14(5): 1027-1031, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634717

RESUMO

BACKGROUND AND AIM: COVID-19 outbreak has created havoc and a quick cure for the disease will be a therapeutic medicine that has usage history in patients to resolve the current pandemic. With technological advancements in Artificial Intelligence (AI) coupled with increased computational power, the AI-empowered drug repurposing can prove beneficial in the COVID-19 scenario. METHODS: The recent literature is studied and analyzed from various sources such as Scopus, Google Scholar, PubMed, and IEEE Xplore databases. The search terms used are 'COVID-19', ' AI ', and 'Drug Repurposing'. RESULTS: AI is implemented in the field design through the generation of the learning-prediction model and performs a quick virtual screening to accurately display the output. With a drug-repositioning strategy, AI can quickly detect drugs that can fight against emerging diseases such as COVID-19. This technology has the potential to improve the drug discovery, planning, treatment, and reported outcomes of the COVID-19 patient, being an evidence-based medical tool. CONCLUSIONS: Thus, there are chances that the application of the AI approach in drug discovery is feasible. With prior usage experiences in patients, few of the old drugs, if shown active against SARS-CoV-2, can be readily applied to treat the COVID-19 patients. With the collaboration of AI with pharmacology, the efficiency of drug repurposing can improve significantly.


Assuntos
Inteligência Artificial , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia
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