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1.
Int Immunopharmacol ; 98: 107831, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: covidwho-1313172

RESUMEN

Explicit hindrance and blockade of the viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is considered one of the most promising and efficient approaches for developing highly potent remedies for COVID-19. However, almost all of the reported viral RdRp inhibitors (either repurposed or new antiviral drugs) lack specific selectivity against the novel coronaviral RdRp and still at a beginning phase of advancement. Herein, I discovered and introduce a new pyrazine derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 RdRp inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). This promising selective specific anti-COVID-19 compound is also deemed to be the first distinctive derivative of favipiravir. Cyanorona-20, the unprecedented nucleoside/nucleotide analog, was designed, synthesized, characterized, computationally studied, and biologically evaluated for its anti-COVID-19 actions (through a precise in vitro anti-COVID-19 assay). The results of the biological assay displayed that cyanorona-20 surprisingly exhibited very high and largely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising guide and lead compound for the design and synthesis of new anti-SARS-CoV-2 and anti-COVID-19 agents through structural modifications and further computational studies. Further appraisal for the improvement of cyanorona-20 medication is a prerequisite requirement in the coming days. In a word, the ascent of the second member (cyanorona-20 "Corona Antidote") of the novel and promising class of anti-COVID-19 pyrazine derivatives would drastically make a medical uprising in the pharmacotherapeutic treatment regimens and protocols of the recently-emerged SARS-CoV-2 infection and its accompanying COVID-19.


Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Inhibidores Enzimáticos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Antivirales/síntesis química , COVID-19/diagnóstico , COVID-19/virología , Diseño Asistido por Computadora , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Interacciones Huésped-Patógeno , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Terapia Molecular Dirigida , ARN Polimerasa Dependiente del ARN/metabolismo , SARS-CoV-2/enzimología , SARS-CoV-2/crecimiento & desarrollo , Relación Estructura-Actividad
2.
Eur J Med Chem ; 223: 113622, 2021 Nov 05.
Artículo en Inglés | MEDLINE | ID: covidwho-1263253

RESUMEN

The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 µM, 4.55 ± 0.2 µM, 1.65 ± 0.05 µM, 3.76 ± 0.79 µM, and 1.11 ± 0.05 µM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 µM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.


Asunto(s)
Acetamidas/síntesis química , Antivirales/síntesis química , Tratamiento Farmacológico de COVID-19 , Inhibidores Enzimáticos/síntesis química , ARN Viral/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , Acetamidas/farmacología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/normas , Alanina/análogos & derivados , Alanina/farmacología , Alanina/normas , Antivirales/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , SARS-CoV-2/genética , Relación Estructura-Actividad
3.
Molecules ; 26(11)2021 Jun 07.
Artículo en Inglés | MEDLINE | ID: covidwho-1259549

RESUMEN

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.


Asunto(s)
Antivirales/síntesis química , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Nucleósidos/análogos & derivados , Nucleósidos/síntesis química , SARS-CoV-2/enzimología , Química Farmacéutica/métodos , Técnicas In Vitro , SARS-CoV-2/efectos de los fármacos
4.
J Med Chem ; 64(9): 5632-5644, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: covidwho-1193564

RESUMEN

To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 µM) of HCoV-229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of HCoV-229E nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.


Asunto(s)
Antivirales/farmacología , Coronavirus Humano 229E/efectos de los fármacos , Coronavirus Humano 229E/enzimología , Endorribonucleasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Ácido Oleanólico/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Línea Celular , Relación Dosis-Respuesta a Droga , Endorribonucleasas/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Ácido Oleanólico/síntesis química , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Proteínas no Estructurales Virales/metabolismo
5.
J Biol Chem ; 296: 100470, 2021.
Artículo en Inglés | MEDLINE | ID: covidwho-1101336

RESUMEN

The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health. Vaccines are ideal solutions to prevent infection, but treatments are also needed for those who have contracted the virus to limit negative outcomes, when vaccines are not applicable. Viruses must cross host cell membranes during their life cycle, creating a dependency on processes involving membrane dynamics. Thus, in this study, we examined whether the synthetic machinery for glycosphingolipids, biologically active components of cell membranes, can serve as a therapeutic target to combat SARS-CoV-2. We examined the antiviral effect of two specific inhibitors of glucosylceramide synthase (GCS): (i) Genz-123346, an analogue of the United States Food and Drug Administration-approved drug Cerdelga and (ii) GENZ-667161, an analogue of venglustat, which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit replication of SARS-CoV-2. Moreover, these inhibitors also disrupt replication of influenza virus A/PR/8/34 (H1N1). Our data imply that synthesis of glycosphingolipids is necessary to support viral life cycles and suggest that GCS inhibitors should be further explored as antiviral therapies.


Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Dioxanos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Glicoesfingolípidos/antagonistas & inhibidores , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Pirrolidinas/farmacología , Quinuclidinas/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/síntesis química , COVID-19/enzimología , COVID-19/virología , Carbamatos/síntesis química , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Membrana Celular/virología , Chlorocebus aethiops , Ensayos Clínicos Fase III como Asunto , Dioxanos/síntesis química , Perros , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Glicoesfingolípidos/biosíntesis , Interacciones Huésped-Patógeno/genética , Humanos , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Gripe Humana/tratamiento farmacológico , Gripe Humana/enzimología , Gripe Humana/virología , Células de Riñón Canino Madin Darby , Pirrolidinas/síntesis química , Quinuclidinas/síntesis química , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/metabolismo , Transducción de Señal , Células Vero , Replicación Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19
6.
Int J Biol Macromol ; 171: 358-365, 2021 Feb 28.
Artículo en Inglés | MEDLINE | ID: covidwho-1013842

RESUMEN

A novel coronavirus disease (COVID-19) caused by SARS-CoV2 has now spread globally. Replication/transcription machinery of this virus consists of RNA-dependent RNA polymerase (nsp12 or RdRp) and its two cofactors nsp7 and nsp8 proteins. Hence, RdRp has emerged as a promising target to control COVID-19. In the present study, we are reporting a novel inhibitor VTRM1.1 against the RdRp protein of SARS CoV2. A series of antivirals were tested for binding to the catalytic residues of the active site of RdRp protein. In-silico screening, molecular mechanics, molecular dynamics simulation (MDS) analysis suggest ribavirin, and remdesivir have good interaction with the binding site of the RdRp protein as compared to other antiviral investigated. Hence, ribavirin and remdesivir were used for the denovo fragments based antiviral design. This design, along with docking and MDS analysis, identified a novel inhibitor VTRM1 that has better interaction with RdRp as compared to their parent molecules. Further, to produce a lead-like compound, retrosynthetic analysis, and combinatorial synthesis were performed, which produces 1000 analogs of VTRM1. These analogs were analysed by docking and MDS analysis that identified VTRM1.1 as a possible lead to inhibit RdRp protein. This lead has a good docking score, favourable binding energy and bind at catalytic residues of the active site of RdRp. The VTRM1.1 also interacts with RdRp in the presence of RNA primer and other cofactors. It was also seen that, VTRM1.1 do not have off-target in human. Therefore, the present study suggests a hybrid inhibitor VTRM1.1 for the RNA-dependent RNA polymerase of SARS CoV2 that may be useful to control infection caused by COVID-19.


Asunto(s)
Antivirales , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos , SARS-CoV-2/enzimología , Antivirales/síntesis química , Antivirales/química , Sitios de Unión , COVID-19 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Simulación de Dinámica Molecular , Dominios Proteicos
7.
Bioorg Chem ; 106: 104488, 2021 01.
Artículo en Inglés | MEDLINE | ID: covidwho-932778

RESUMEN

In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.


Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos , Animales , Antivirales/síntesis química , Antivirales/farmacología , COVID-19/epidemiología , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Pandemias , SARS-CoV-2/efectos de los fármacos
8.
J Enzyme Inhib Med Chem ; 35(1): 145-151, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: covidwho-826697

RESUMEN

There were severe panics caused by Severe Acute Respiratory Syndrome (SARS) and Middle-East Respiratory Syndrome-Coronavirus. Therefore, researches targeting these viruses have been required. Coronaviruses (CoVs) have been rising targets of some flavonoids. The antiviral activity of some flavonoids against CoVs is presumed directly caused by inhibiting 3C-like protease (3CLpro). Here, we applied a flavonoid library to systematically probe inhibitory compounds against SARS-CoV 3CLpro. Herbacetin, rhoifolin and pectolinarin were found to efficiently block the enzymatic activity of SARS-CoV 3CLpro. The interaction of the three flavonoids was confirmed using a tryptophan-based fluorescence method, too. An induced-fit docking analysis indicated that S1, S2 and S3' sites are involved in binding with flavonoids. The comparison with previous studies showed that Triton X-100 played a critical role in objecting false positive or overestimated inhibitory activity of flavonoids. With the systematic analysis, the three flavonoids are suggested to be templates to design functionally improved inhibitors.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Proteínas Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/aislamiento & purificación , Cisteína Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Flavonoides/síntesis química , Flavonoides/química , Humanos , Estructura Molecular , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Relación Estructura-Actividad , Proteínas Virales/aislamiento & purificación , Proteínas Virales/metabolismo
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