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1.
Molecules ; 26(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810416

RESUMEN

The current COronaVIrus Disease 19 (COVID-19) pandemic caused by SARS-CoV-2 infection is enormously affecting the worldwide health and economy. In the wait for an effective global immunization, the development of a specific therapeutic protocol to treat COVID-19 patients is clearly necessary as a short-term solution of the problem. Drug repurposing and herbal medicine represent two of the most explored strategies for an anti-COVID-19 drug discovery. Clove (Syzygium aromaticum L.) is a well-known culinary spice that has been used for centuries in folk medicine in many disorders. Interestingly, traditional medicines have used clove since ancient times to treat respiratory ailments, whilst clove ingredients show antiviral and anti-inflammatory properties. Other interesting features are the clove antithrombotic, immunostimulatory, and antibacterial effects. Thus, in this review, we discuss the potential role of clove in the frame of anti-COVID-19 therapy, focusing on the antiviral, anti-inflammatory, and antithrombotic effects of clove and its molecular constituents described in the scientific literature.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antivirales/farmacología , Fibrinolíticos/farmacología , Syzygium/química , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Antiinflamatorios no Esteroideos/química , Antivirales/química , /prevención & control , Medicina de Hierbas/métodos , Humanos , Fitoquímicos/química , Fitoquímicos/farmacología , Plantas Medicinales/química
2.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804129

RESUMEN

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.


Asunto(s)
Antivirales/química , Metales/química , Metisazona/química , Simulación del Acoplamiento Molecular , /química , Antivirales/metabolismo , Calcio/química , Calcio/metabolismo , /metabolismo , /metabolismo , /metabolismo , Diseño de Fármacos , Humanos , Hierro/química , Hierro/metabolismo , Magnesio/química , Magnesio/metabolismo , Manganeso/química , Manganeso/metabolismo , Metales/metabolismo , Metisazona/metabolismo , Modelos Moleculares , Simulación de Dinámica Molecular , Unión Proteica , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Zinc/química , Zinc/metabolismo
3.
Molecules ; 26(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806967

RESUMEN

Bats are unique in their potential to serve as reservoir hosts for intracellular pathogens. Recently, the impact of COVID-19 has relegated bats from biomedical darkness to the frontline of public health as bats are the natural reservoir of many viruses, including SARS-Cov-2. Many bat genomes have been sequenced recently, and sequences coding for antimicrobial peptides are available in the public databases. Here we provide a structural analysis of genome-predicted bat cathelicidins as components of their innate immunity. A total of 32 unique protein sequences were retrieved from the NCBI database. Interestingly, some bat species contained more than one cathelicidin. We examined the conserved cysteines within the cathelin-like domain and the peptide portion of each sequence and revealed phylogenetic relationships and structural dissimilarities. The antibacterial, antifungal, and antiviral activity of peptides was examined using bioinformatic tools. The peptides were modeled and subjected to docking analysis with the region binding domain (RBD) region of the SARS-CoV-2 Spike protein. The appearance of multiple forms of cathelicidins verifies the complex microbial challenges encountered by these species. Learning more about antiviral defenses of bats and how they drive virus evolution will help scientists to investigate the function of antimicrobial peptides in these species.


Asunto(s)
Catelicidinas/química , Catelicidinas/farmacología , Quirópteros/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Antivirales/química , Antivirales/farmacología , Sitios de Unión , Catelicidinas/genética , Catelicidinas/metabolismo , Biología Computacional/métodos , Simulación por Computador , Genoma , Simulación del Acoplamiento Molecular , Filogenia
4.
Molecules ; 26(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33807029

RESUMEN

Natural products are gaining more interest recently, much of which focuses on those derived from medicinal plants. The common chicory (Cichorium intybus L.), of the Astraceae family, is a prime example of this trend. It has been proven to be a feasible source of biologically relevant elements (K, Fe, Ca), vitamins (A, B1, B2, C) as well as bioactive compounds (inulin, sesquiterpene lactones, coumarin derivatives, cichoric acid, phenolic acids), which exert potent pro-health effects on the human organism. It displays choleretic and digestion-promoting, as well as appetite-increasing, anti-inflammatory and antibacterial action, all owing to its varied phytochemical composition. Hence, chicory is used most often to treat gastrointestinal disorders. Chicory was among the plants with potential against SARS-CoV-2, too. To this and other ends, roots, herb, flowers and leaves are used. Apart from its phytochemical applications, chicory is also used in gastronomy as a coffee substitute, food or drink additive. The aim of this paper is to present, in the light of the recent literature, the chemical composition and properties of chicory.


Asunto(s)
Achicoria/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Antiparasitarios/química , Antiparasitarios/farmacología , Antivirales/química , Antivirales/farmacología , Achicoria/fisiología , Culinaria , Hipersensibilidad a los Alimentos/etiología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Plantas Medicinales/química
5.
Molecules ; 26(6)2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33809963

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome corona virus-2 (SARS-CoV-2), is the most important health issue, internationally. With no specific and effective antiviral therapy for COVID-19, new or repurposed antiviral are urgently needed. Phytochemicals pose a ray of hope for human health during this pandemic, and a great deal of research is concentrated on it. Phytochemicals have been used as antiviral agents against several viruses since they could inhibit several viruses via different mechanisms of direct inhibition either at the viral entry point or the replication stages and via immunomodulation potentials. Recent evidence also suggests that some plants and its components have shown promising antiviral properties against SARS-CoV-2. This review summarizes certain phytochemical agents along with their mode of actions and potential antiviral activities against important viral pathogens. A special focus has been given on medicinal plants and their extracts as well as herbs which have shown promising results to combat SARS-CoV-2 infection and can be useful in treating patients with COVID-19 as alternatives for treatment under phytotherapy approaches during this devastating pandemic situation.


Asunto(s)
Antivirales/farmacología , Fitoquímicos/farmacología , Plantas Medicinales/química , /patogenicidad , Antivirales/química , Humanos , India , Fitoquímicos/química , Extractos Vegetales/farmacología , /química
6.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808940

RESUMEN

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 µM and 99% at 15 µM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 µM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Oxiesteroles/química , Oxiesteroles/farmacología , /efectos de los fármacos , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Ratones , Proteínas de la Nucleocápside/efectos de los fármacos , Oxiesteroles/administración & dosificación , Oxiesteroles/farmacocinética , Células Vero , Replicación Viral/efectos de los fármacos
7.
Molecules ; 26(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668428

RESUMEN

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.


Asunto(s)
Antivirales , Reposicionamiento de Medicamentos , Nucleósidos , Virus del SRAS/metabolismo , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Animales , Antivirales/química , Antivirales/uso terapéutico , /metabolismo , Humanos , Nucleósidos/química , Nucleósidos/uso terapéutico , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/metabolismo
8.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669720

RESUMEN

Coronavirus desease 2019 (COVID-19) is responsible for more than 1.80 M deaths worldwide. A Quantitative Structure-Activity Relationships (QSAR) model is developed based on experimental pIC50 values reported for a structurally diverse dataset. A robust model with only five descriptors is found, with values of R2 = 0.897, Q2LOO = 0.854, and Q2ext = 0.876 and complying with all the parameters established in the validation Tropsha's test. The analysis of the applicability domain (AD) reveals coverage of about 90% for the external test set. Docking and molecular dynamic analysis are performed on the three most relevant biological targets for SARS-CoV-2: main protease, papain-like protease, and RNA-dependent RNA polymerase. A screening of the DrugBank database is executed, predicting the pIC50 value of 6664 drugs, which are IN the AD of the model (coverage = 79%). Fifty-seven possible potent anti-COVID-19 candidates with pIC50 values > 6.6 are identified, and based on a pharmacophore modelling analysis, four compounds of this set can be suggested as potent candidates to be potential inhibitors of SARS-CoV-2. Finally, the biological activity of the compounds was related to the frontier molecular orbitals shapes.


Asunto(s)
Antivirales/química , Inhibidores de Cisteína Proteinasa/química , Bases de Datos de Compuestos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , /enzimología , Antivirales/uso terapéutico , /antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Relación Estructura-Actividad Cuantitativa , /química
9.
Molecules ; 26(4)2021 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-33670436

RESUMEN

Quinoxalines, a class of N-heterocyclic compounds, are important biological agents, and a significant amount of research activity has been directed towards this class. They have several prominent pharmacological effects like antifungal, antibacterial, antiviral, and antimicrobial. Quinoxaline derivatives have diverse therapeutic uses and have become the crucial component in drugs used to treat cancerous cells, AIDS, plant viruses, schizophrenia, certifying them a great future in medicinal chemistry. Due to the current pandemic situation caused by SARS-COVID 19, it has become essential to synthesize drugs to combat deadly pathogens (bacteria, fungi, viruses) for now and near future. Since quinoxalines is an essential moiety to treat infectious diseases, numerous synthetic routes have been developed by researchers, with a prime focus on green chemistry and cost-effective methods. This review paper highlights the various synthetic routes to prepare quinoxaline and its derivatives, covering the literature for the last two decades. A total of 31 schemes have been explained using the green chemistry approach, cost-effective methods, and quinoxaline derivatives' therapeutic uses.


Asunto(s)
Antivirales , Pandemias , Quinoxalinas , /metabolismo , Antivirales/síntesis química , Antivirales/química , Antivirales/uso terapéutico , Humanos , Quinoxalinas/síntesis química , Quinoxalinas/química , Quinoxalinas/uso terapéutico
10.
Molecules ; 26(4)2021 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-33672163

RESUMEN

To date very few promising leads from natural products (NP) secondary metabolites with antiviral and immunomodulatory properties have been identified for promising/potential intervention for COVID-19. Using in-silico docking studies and genome based various molecular targets, and their in vitro anti-SARS CoV-2 activities against whole cell and/or selected protein targets, we select a few compounds of interest, which can be used as potential leads to counteract effects of uncontrolled innate immune responses, in particular those related to the cytokine storm. A critical factor for prevention and treatment of SARS-CoV-2 infection relates to factors independent of viral infection or host response. They include population-related variables such as concurrent comorbidities and genetic factors critically relevant to COVID-19 health disparities. We discuss population risk factors related to SARS-CoV-2. In addition, we focus on virulence related to glucose-6-phosphate dehydrogenase deficiency (G6PDd), the most common human enzymopathy. Review of data on the response of individuals and communities with high prevalence of G6PDd to NP, prompts us to propose the rationale for a population-specific management approach to rationalize design of therapeutic interventions of SARS-CoV-2 infection, based on use of NP. This strategy may lead to personalized approaches and improve disease-related outcomes.


Asunto(s)
Productos Biológicos , /tratamiento farmacológico , Antivirales/química , Antivirales/uso terapéutico , Productos Biológicos/química , Productos Biológicos/uso terapéutico , Deficiencia de Glucosafosfato Deshidrogenasa/tratamiento farmacológico , Deficiencia de Glucosafosfato Deshidrogenasa/epidemiología , Humanos
11.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672721

RESUMEN

The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.


Asunto(s)
Antivirales/química , Inhibidores de Cisteína Proteinasa/química , Simulación del Acoplamiento Molecular , /enzimología , Antivirales/uso terapéutico , /antagonistas & inhibidores , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos
12.
Nat Struct Mol Biol ; 28(3): 319-325, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33674802

RESUMEN

The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.


Asunto(s)
Antivirales/farmacología , /química , Inhibidores Enzimáticos/farmacología , Suramina/farmacología , Animales , Antivirales/química , Antivirales/metabolismo , Sitios de Unión , Dominio Catalítico , Chlorocebus aethiops , Microscopía por Crioelectrón , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Conformación Proteica , ARN Viral/química , ARN Viral/metabolismo , Suramina/química , Suramina/metabolismo , Células Vero , Replicación Viral/efectos de los fármacos
13.
Emerg Microbes Infect ; 10(1): 481-492, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33691601

RESUMEN

The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.


Asunto(s)
Antivirales/farmacología , /antagonistas & inhibidores , Sistema Respiratorio/virología , /efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacocinética , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Quimioterapia Combinada , Femenino , Ratones , Ratones Endogámicos BALB C , Profármacos/farmacología , Ratas , Ratas Sprague-Dawley , Células Vero
14.
J Chem Inf Model ; 61(3): 1402-1411, 2021 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-33655751

RESUMEN

SARS-CoV-2 is a positive-sense RNA virus that requires an RNA-dependent RNA polymerase (RdRp) for replication of its viral genome. Nucleoside analogs such as Remdesivir and ß-d-N4-hydroxycytidine are antiviral candidates and may function as chain terminators or induce viral mutations, thus impairing RdRp function. Recently disclosed Cryo-EM structures of apo, RNA-bound, and inhibitor-bound SARS-CoV-2 RdRp provided insight into the inhibitor-bound structure by capturing the enzyme with its reaction product: Remdesivir covalently bound to the RNA primer strand. To gain a structural understanding of the binding of this and several other nucleoside analogs in the precatalytic state, molecular models were developed that predict the noncovalent interactions to a complex of SARS-CoV-2 RdRp, RNA, and catalytic metal cations. MM-GBSA evaluation of these interactions is consistent with resistance-conferring mutations and existing structure-activity relationship (SAR) data. Therefore, this approach may yield insights into antiviral mechanisms and guide the development of experimental drugs for COVID-19 treatment.


Asunto(s)
/tratamiento farmacológico , Nucleósidos/análogos & derivados , Nucleósidos/farmacología , ARN Viral/metabolismo , /efectos de los fármacos , Antivirales/química , Antivirales/farmacología , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , /metabolismo
15.
Int J Nanomedicine ; 16: 1789-1804, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33688191

RESUMEN

Background: SARS-COVID-2 has recently been one of the most life-threatening problems which urgently needs new therapeutic antiviral agents, especially those of herbal origin. Purpose: The study aimed to load acaciin (ACA) into the new self-assembled nanofibers (NFs) followed by investigating their possible antiviral effect against bovine coronavirus (BCV) as a surrogate model for SARS-COV-2. Methods: ACA was identified using 1H-NMR and DEPT-Q 13C-NMR spectroscopy, the molecular docking study was performed using Autodock 4 and a modification of the traditional solvent injection method was applied for the synthesis of the biodegradable NFs. Different characterization techniques were used to inspect the formation of the NFs, which is followed by antiviral investigation against BCV as well as MTT assay using MDBK cells. Results: Core/shell NFs, ranging between 80-330 nm with tiny thorn-like branches, were formed which attained an enhanced encapsulation efficiency (97.5 ± 0.53%, P<0.05) and a dual controlled release (a burst release of 65% at 1 h and a sustained release up to >24 h). The antiviral investigation of the formed NFs revealed a significant inhibition of 98.88 ± 0.16% (P<0.05) with IC50 of 12.6 µM against BCV cells. Conclusion: The results introduced a new, time/cost-saving strategy for the synthesis of biodegradable NFs without the need for electric current or hazardous cross-linking agents. Moreover, it provided an innovative avenue for the discovery of drugs of herbal origin for the fight against SARS-CoV-2 infection.


Asunto(s)
Coronavirus Bovino/efectos de los fármacos , Glicósidos/farmacología , Nanofibras/química , /efectos de los fármacos , Antivirales/química , Antivirales/farmacología , /virología , Línea Celular , Glicósidos/química , Glicósidos/aislamiento & purificación , Glicósidos/uso terapéutico , Humanos , Ligandos , Modelos Biológicos , Simulación del Acoplamiento Molecular , Nanofibras/ultraestructura , Solventes , Rayos Ultravioleta
17.
Cells ; 10(2)2021 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-33669990

RESUMEN

Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent histone deacetylases that incorporate complex functions in the mechanisms of cell physiology. Mammals have seven distinct members of the SIRT family (SIRT1-7), which play an important role in a well-maintained network of metabolic pathways that control and adapt the cell to the environment, energy availability and cellular stress. Until recently, very few studies investigated the role of SIRTs in modulating viral infection and progeny. Recent studies have demonstrated that SIRT1 and SIRT2 are promising antiviral targets because of their specific connection to numerous metabolic and regulatory processes affected during infection. In the present review, we summarize some of the recent progress in SIRTs biochemistry and their emerging function as antiviral targets. We also discuss the potential of natural polyphenol-based SIRT modulators to control their functional roles in several diseases including viral infections.


Asunto(s)
Redes y Vías Metabólicas , Sirtuinas/metabolismo , Virosis/metabolismo , Animales , Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Modelos Moleculares , Terapia Molecular Dirigida , NAD/metabolismo , Sirtuinas/análisis , Virosis/tratamiento farmacológico , Virus/efectos de los fármacos , Virus/metabolismo
18.
Viruses ; 13(2)2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33672054

RESUMEN

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (Mpro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 Mpro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 Mpro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 Mpro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 Mpro antagonist with higher affinity and drug-likeness.


Asunto(s)
Antivirales/química , Echinacea/química , Inhibidores de Proteasas/química , Sitios de Unión , Descubrimiento de Drogas , Flavonas/química , Fructanos/química , Glicósidos/química , Inulina/química , Simulación del Acoplamiento Molecular , Fitoquímicos/química , Unión Proteica , Ácido Quínico/análogos & derivados , Ácido Quínico/química
19.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652639

RESUMEN

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.


Asunto(s)
Catequina/análogos & derivados , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Proteínas del Envoltorio Viral/genética , Antivirales/química , Antivirales/farmacología , Catequina/química , Catequina/farmacología , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/virología , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Polifenoles/química , Polifenoles/farmacología , Té/química , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Internalización del Virus/efectos de los fármacos
20.
Sci Rep ; 11(1): 6248, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33737523

RESUMEN

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/química , Ribavirina/química , Glicoproteína de la Espiga del Coronavirus/química , Adenosina Monofosfato/química , Alanina/química , Compuestos de Anilina/química , Evaluación Preclínica de Medicamentos , Genoma Viral , Simulación del Acoplamiento Molecular , Sulfonamidas/química
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