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1.
Molecules ; 25(19)2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33036293

RESUMO

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.


Assuntos
Antivirais/síntese química , Betacoronavirus/enzimologia , Hidrazonas/síntese química , Inibidores de Proteases/síntese química , Pirazinas/síntese química , Pirazóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Descoberta de Drogas , Humanos , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Pirazinas/farmacologia , Pirazóis/farmacologia , Termodinâmica , Interface Usuário-Computador , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
2.
Org Lett ; 22(21): 8430-8435, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33085486

RESUMO

We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Amidinas/química , Antivirais/química , Antivirais/síntese química , Monofosfato de Adenosina/síntese química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Alanina/síntese química , Alanina/química , Alanina/uso terapêutico , Antivirais/uso terapêutico , Técnicas de Química Sintética , Infecções por Coronavirus/tratamento farmacológico , Ciclização , Pandemias , Pneumonia Viral/tratamento farmacológico
3.
Molecules ; 25(19)2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32987757

RESUMO

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fármacos do Sistema Respiratório/uso terapêutico , Doença Aguda , Anti-Inflamatórios/síntese química , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptídeos/síntese química , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/prevenção & controle , Insuficiência Respiratória/virologia , Fármacos do Sistema Respiratório/síntese química , Relação Estrutura-Atividade
4.
Nat Rev Immunol ; 20(10): 594-602, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913283

RESUMO

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Assuntos
Infecções por Coronavirus/epidemiologia , Cooperação Internacional , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Sociedades Científicas/organização & administração , Antivirais/síntese química , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Relações Comunidade-Instituição , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Saúde Global/tendências , Humanos , Educação de Pacientes como Assunto/organização & administração , Equipamento de Proteção Individual/provisão & distribução , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/terapia , Síndrome Respiratória Aguda Grave/virologia , Distância Social , Vacinas Virais/biossíntese
5.
Bioorg Med Chem Lett ; 30(20): 127472, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781216

RESUMO

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4-(3-Chloro-4-fluorophenyl)-N6-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC50 = 0.157 µM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.


Assuntos
Compostos de Anilina/farmacologia , Antivirais/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinazolinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/toxicidade , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular , Chlorocebus aethiops , Cricetulus , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/toxicidade , Ratos , Relação Estrutura-Atividade
6.
Mucosal Immunol ; 13(6): 877-891, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32820248

RESUMO

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.


Assuntos
Anticorpos Antivirais/biossíntese , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Pneumonia Viral/imunologia , Vacinas Virais/biossíntese , Animais , Animais Geneticamente Modificados , Antivirais/síntese química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Betacoronavirus/fisiologia , Gatos , Quirópteros , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Cricetulus , Feminino , Furões , Haplorrinos , Humanos , Masculino , Camundongos , Organoides/efeitos dos fármacos , Organoides/imunologia , Organoides/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Especificidade da Espécie , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/administração & dosagem
7.
Biochemistry ; 59(33): 3038-3043, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32786401

RESUMO

The COVID-19 pandemic threatens to overwhelm healthcare systems around the world. The only current FDA-approved treatment, which directly targets the virus, is the ProTide prodrug remdesivir. In its activated form, remdesivir prevents viral replication by inhibiting the essential RNA-dependent RNA polymerase. Like other ProTide prodrugs, remdesivir contains a chiral phosphorus center. The initial selection of the (SP)-diastereomer for remdesivir was reportedly due to the difficulty in producing the pure (RP)-diastereomer of the required precursor. However, the two currently known enzymes responsible for the initial activation step of remdesivir are each stereoselective and show differential tissue distribution. Given the ability of the COVID-19 virus to infect a wide array of tissue types, inclusion of the (RP)-diastereomer may be of clinical significance. To help overcome the challenge of obtaining the pure (RP)-diastereomer of remdesivir, we have developed a novel chemoenzymatic strategy that utilizes a stereoselective variant of the phosphotriesterase from Pseudomonas diminuta to enable the facile isolation of the pure (RP)-diastereomer of the chiral precursor for the chemical synthesis of the (RP)-diastereomer of remdesivir.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/síntese química , Monofosfato de Adenosina/síntese química , Alanina/síntese química , Betacoronavirus , Caulobacteraceae/enzimologia , Infecções por Coronavirus , Humanos , Estrutura Molecular , Pandemias , Hidrolases de Triester Fosfórico/química , Pneumonia Viral , RNA Replicase/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
8.
Science ; 369(6504): 725-730, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32764073

RESUMO

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2'- and C4'-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.


Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Nucleosídeos/síntese química , Antineoplásicos/química , Antivirais/química , Nucleosídeos/química
9.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661235

RESUMO

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Proteínas de Choque Térmico/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Antivirais/síntese química , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/agonistas , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/agonistas , Ribonucleoproteínas Nucleares Heterogêneas/antagonistas & inibidores , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Interações Hospedeiro-Patógeno/genética , Humanos , Terapia de Alvo Molecular/métodos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Transcrição Genética/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
13.
Am J Trop Med Hyg ; 102(6): 1181-1183, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-596857

RESUMO

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.


Assuntos
Betacoronavirus/patogenicidade , Defesa Civil/organização & administração , Infecções por Coronavirus/epidemiologia , Cooperação Internacional/legislação & jurisprudência , Pandemias , Pneumonia Viral/epidemiologia , Antivirais/síntese química , Antivirais/uso terapêutico , Ásia/epidemiologia , Betacoronavirus/efeitos dos fármacos , Técnicas de Laboratório Clínico/normas , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Europa (Continente)/epidemiologia , Humanos , Oriente Médio/epidemiologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/biossíntese , Vacinas Virais/uso terapêutico
16.
Am J Trop Med Hyg ; 102(6): 1181-1183, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-108902

RESUMO

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.


Assuntos
Betacoronavirus/patogenicidade , Defesa Civil/organização & administração , Infecções por Coronavirus/epidemiologia , Cooperação Internacional/legislação & jurisprudência , Pandemias , Pneumonia Viral/epidemiologia , Antivirais/síntese química , Antivirais/uso terapêutico , Ásia/epidemiologia , Betacoronavirus/efeitos dos fármacos , Técnicas de Laboratório Clínico/normas , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Europa (Continente)/epidemiologia , Humanos , Oriente Médio/epidemiologia , Pandemias/prevenção & controle , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Vacinas Virais/biossíntese , Vacinas Virais/uso terapêutico
19.
Artigo em Inglês | MEDLINE | ID: mdl-32310031

RESUMO

Synthesis of 1-((4 R,5S,6R,7R)-5,6-dihydroxy-7-(hydroxymethyl)spiro[2.4]heptan-4-yl)pyrimidine-2,4(1H,3H)-dione (12) and its phosphoramidate prodrug 18 is reported. The synthesis of the targeted compound 12 was initiated from triol 1. By the introduction of a substituent methylene group at 6-position of 4, followed by Simmons-Smith cyclopropanation and amination, key intermediate 10 was synthesized. The intermediate amine 10 was utilized to synthesize the nucleoside 12. Furthermore, the nucleoside 12 was derivatized to 2'-α-hydroxy-2'-ß-methyl (23) and 2'-α-fluoro-2'-ß-methyl (27) analogs. All synthesized derivatives of spiro-cyclopropyl carbocyclic uridine analogs 12, 18, 23 and 27 were evaluated for anti-HCV activity, but none of the compounds, reported in this article show any anti-HCV activity.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Uridina/síntese química , Uridina/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Uridina/análogos & derivados , Replicação Viral/efeitos dos fármacos
20.
Arch Virol ; 165(6): 1385-1396, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32346764

RESUMO

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3ß-[(N-(2-hydroxyethyl)aminoacetyl]amino-3-deoxydigitoxigenin) and C11 (3ß-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (ß) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains.


Assuntos
Antivirais/farmacologia , Cardenolídeos/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Antivirais/síntese química , Cardenolídeos/síntese química , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Células Vero
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