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1.
Bioorg Med Chem Lett ; 42: 128067, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33957246

RESUMEN

The outbreak of coronavirus (CoV) disease 2019 (COVID-19) caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has turned into a pandemic. The enzyme 3C-like protease (3CLpro) is essential for the maturation of viral polyproteins in SARS-CoV-2 and is therefore regarded as a key drug target for treating the disease. To identify 3CLpro inhibitors that can suppress SARS-CoV-2 replication, we performed a virtual screening of 500,282 compounds in a Korean compound bank. We then subjected the top computational hits to inhibitory assays against 3CLpro in vitro, leading to the identification of a class of non-covalent inhibitors. Among these inhibitors, compound 7 showed an EC50 of 39.89 µM against SARS-CoV-2 and CC50 of 453.5 µM. This study provides candidates for the optimization of potent 3CLpro inhibitors showing antiviral effects against SARS-CoV-2.


Asunto(s)
Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , SARS-CoV-2/enzimología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antivirales/metabolismo , Chlorocebus aethiops , Proteasas 3C de Coronavirus/metabolismo , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/metabolismo , Unión Proteica , República de Corea , Bibliotecas de Moléculas Pequeñas/metabolismo , Células Vero
2.
ACS Nano ; 15(1): 857-872, 2021 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-33373194

RESUMEN

The infectious SARS-CoV-2 causes COVID-19, which is now a global pandemic. Aiming for effective treatments, we focused on the key drug target, the viral 3C-like (3CL) protease. We modeled a big dataset with 42 SARS-CoV-2 3CL protease-ligand complex structures from ∼98.7% similar SARS-CoV 3CL protease with abundant complex structures. The diverse flexible active site conformations identified in the dataset were clustered into six protease pharmacophore clusters (PPCs). For the PPCs with distinct flexible protease active sites and diverse interaction environments, we identified pharmacophore anchor hotspots. A total of 11 "PPC consensus anchors" (a distinct set observed in each PPC) were observed, of which three "PPC core anchors" EHV2, HV1, and V3 are strongly conserved across PPCs. The six PPC cavities were then applied in virtual screening of 2122 FDA drugs for repurposing, using core anchor-derived "PPC scoring S" to yield seven drug candidates. Experimental testing by SARS-CoV-2 3CL protease inhibition assay and antiviral cytopathic effect assays discovered active hits, Boceprevir and Telaprevir (HCV drugs) and Nelfinavir (HIV drug). Specifically, Boceprevir showed strong protease inhibition with micromolar IC50 of 1.42 µM and an antiviral activity with EC50 of 49.89 µM, whereas Telaprevir showed moderate protease inhibition only with an IC50 of 11.47 µM. Nelfinavir solely showed antiviral activity with a micromolar EC50 value of 3.28 µM. Analysis of binding mechanisms of protease inhibitors revealed the role of PPC core anchors. Our PPCs revealed the flexible protease active site conformations, which successfully enabled drug repurposing.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/química , Reposicionamiento de Medicamentos , SARS-CoV-2/enzimología , Animales , Antivirales/farmacología , Dominio Catalítico , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Nelfinavir/farmacología , Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacología , Conformación Proteica , Glicoproteína de la Espiga del Coronavirus/química , Células Vero
3.
Antiviral Res ; 182: 104927, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32910955

RESUMEN

Feline infectious peritonitis (FIP) which is caused by feline infectious peritonitis virus (FIPV), a variant of feline coronavirus (FCoV), is a member of family Coronaviridae, together with severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. So far, neither effective vaccines nor approved antiviral therapeutics are currently available for the treatment of FIPV infection. Both human and animal CoVs shares similar functional proteins, particularly the 3CL protease (3CLpro), which plays the pivotal role on viral replication. We investigated the potential drug-liked compounds and their inhibitory interaction on the 3CLpro active sites of CoVs by the structural-bases virtual screening. Fluorescence resonance energy transfer (FRET) assay revealed that three out of twenty-eight compounds could hamper FIPV 3CLpro activities with IC50 of 3.57 ± 0.36 µM to 25.90 ± 1.40 µM, and Ki values of 2.04 ± 0.08 to 15.21 ± 1.76 µM, respectively. Evaluation of antiviral activity using cell-based assay showed that NSC629301 and NSC71097 could strongly inhibit the cytopathic effect and also reduced replication of FIPV in CRFK cells in all examined conditions with the low range of EC50 (6.11 ± 1.90 to 7.75 ± 0.48 µM and 1.99 ± 0.30 to 4.03 ± 0.60 µM, respectively), less than those of ribavirin and lopinavir. Analysis of FIPV 3CLpro-ligand interaction demonstrated that the selected compounds reacted to the crucial residues (His41 and Cys144) of catalytic dyad. Our investigations provide a fundamental knowledge for the further development of antiviral agents and increase the number of anti-CoV agent pools for feline coronavirus and other related CoVs.


Asunto(s)
Antivirales/farmacología , Coronavirus Felino/efectos de los fármacos , Coronavirus Felino/enzimología , Inhibidores de Cisteína Proteinasa/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Betacoronavirus/efectos de los fármacos , Betacoronavirus/enzimología , COVID-19 , Dominio Catalítico , Gatos , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Cisteína Endopeptidasas/química , Evaluación Preclínica de Medicamentos/métodos , Peritonitis Infecciosa Felina/tratamiento farmacológico , Peritonitis Infecciosa Felina/virología , Humanos , Concentración 50 Inhibidora , Cinética , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/enzimología , Modelos Moleculares , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , SARS-CoV-2 , Proteínas no Estructurales Virales/química , Replicación Viral/efectos de los fármacos
4.
Antiviral Res ; 174: 104697, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31863793

RESUMEN

The computational search of chemical libraries has been used as a powerful tool for the rapid discovery of candidate compounds. To find small molecules with anti-feline infectious peritonitis virus (FIPV) properties, we utilized a virtual screening technique to identify the active site on the viral protease for the binding of the available natural compounds. The protease 3CL (3CLpro) plays an important role in the replication cycle of FIPV and other viruses within the family Coronaviridae. The 15 best-ranked candidate consensus compounds, based on three docking tools, were evaluated for further assays. The protease inhibitor assay on recombinant FIPV 3CLpro was performed to screen the inhibitory effect of the candidate compounds with IC50 ranging from 6.36 ± 2.15 to 78.40 ± 2.60 µM. As determined by the cell-based assay, the compounds NSC345647, NSC87511, and NSC343256 showed better EC50 values than the broad-spectrum antiviral drug ribavirin and the protease inhibitor lopinavir, under all the test conditions including pre-viral entry, post-viral entry, and prophylactic activity. The NSC87511 particularly yielded the best selective index (>4; range of SI = 13.80-22.90). These results indicated that the natural small-molecular compounds specifically targeted the 3CLpro of FIPV and inhibited its replication. Structural modification of these compounds may generate a higher anti-viral potency for the further development of a novel therapy against FIP.


Asunto(s)
Antivirales/química , Coronavirus Felino/enzimología , Peritonitis Infecciosa Felina/virología , Péptido Hidrolasas/química , Inhibidores de Proteasas/química , Proteínas Virales/química , Animales , Antivirales/farmacología , Dominio Catalítico , Gatos , Simulación por Computador , Coronavirus Felino/química , Coronavirus Felino/efectos de los fármacos , Coronavirus Felino/genética , Evaluación Preclínica de Medicamentos , Cinética , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/farmacología , Ribavirina/química , Ribavirina/farmacología , Proteínas Virales/genética , Proteínas Virales/metabolismo
5.
J Tradit Complement Med ; 1(1): 41-50, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24716104

RESUMEN

Development of anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) agents is pivotal to prevent the reemergence of the life-threatening disease, SARS. In this study, more than 200 extracts from Chinese medicinal herbs were evaluated for anti-SARS-CoV activities using a cell-based assay that measured SARS-CoV-induced cytopathogenic effect (CPE) in vitro on Vero E6 cells. Six herbal extracts, one each from Gentianae Radix ( lóng dǎn; the dried rhizome of Gentiana scabra), Dioscoreae Rhizoma ( shan yào; the tuber of Dioscorea batatas), Cassiae Semen ( jué míng zǐ; the dried seed of Cassia tora) and Loranthi Ramus ( sang jì sheng; the dried stem, with leaf of Taxillus chinensis) (designated as GSH, DBM, CTH and TCH, respectively), and two from Rhizoma Cibotii ( gǒu jǐ; the dried rhizome of Cibotium barometz) (designated as CBE and CBM), were found to be potent inhibitors of SARS-CoV at concentrations between 25 and 200 µg/ml. The concentrations of the six extracts needed to inhibit 50% of Vero E6 cell proliferation (CC50) and 50% of viral replication (EC50) were determined. The resulting selective index values (SI = CC50/EC50) of the most effective extracts CBE, GSH, DBM, CTH and TCH were > 59.4, > 57.5, > 62.1, > 59.4, and > 92.9, respectively. Among these extracts, CBM and DBM also showed significant inhibition of SARS-CoV 3CL protease activity with IC50 values of 39 µg/ml and 44 µg/ml, respectively. Our findings suggest that these six herbal extracts may have potential as candidates for future development of anti-SARS therapeutics.AbbreviationsSARS,severe acute respiratory syndromeCoV,coronavirusCPE,cytopathogenic effectTCM,traditional Chinese medicine.

6.
FEBS Lett ; 583(3): 549-55, 2009 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-19166843

RESUMEN

Picornaviruses (PV) and coronaviruses (CoV) are positive-stranded RNA viruses which infect millions of people worldwide each year, resulting in a wide range of clinical outcomes. As reported in this study, using high throughput screening against approximately 6800 small molecules, we have identified several novel inhibitors of SARS-CoV 3CL(pro) with IC(50) of low microM. Interestingly, one of them equally inhibited both 3C(pro) and 3CL(pro) from PV and CoV, respectively. Using computer modeling, the structural features of these compounds as individual and common protease inhibitors were elucidated to enhance our knowledge for developing anti-viral agents against PV and CoV.


Asunto(s)
Coronavirus/efectos de los fármacos , Coronavirus/enzimología , Péptido Hidrolasas/metabolismo , Picornaviridae/efectos de los fármacos , Picornaviridae/enzimología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Secuencia de Aminoácidos , Simulación por Computador , Secuencia Conservada , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Datos de Secuencia Molecular , Péptido Hidrolasas/química , Unión Proteica , Estructura Terciaria de Proteína , Alineación de Secuencia , Relación Estructura-Actividad
7.
J Med Chem ; 50(17): 4087-95, 2007 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-17663539

RESUMEN

In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.


Asunto(s)
Plantas Medicinales , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Terpenos/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/química , Lignanos/química , Modelos Moleculares , Triterpenos Pentacíclicos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Relación Estructura-Actividad , Terpenos/química , Triterpenos/química , Células Vero , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Replicación Viral , Ácido Betulínico
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