Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 23
Filter
1.
J Antibiot (Tokyo) ; 75(5): 258-267, 2022 May.
Article in English | MEDLINE | ID: covidwho-1728737

ABSTRACT

A series of lupane-, oleanane- and dammarane-based triterpenoids with 3ß-amino, A-ring azepano- and 3,4-seco-fragments has been synthesized and evaluated for antiviral activity against influenza A(H1N1) virus. It was found that azepanodipterocarpol 8 and 3ß-amino-28-oxoallobetulin 11 showed antiviral activity with IC50 1.1 and 2.6 µg ml-1, and selectivity index of 19 and 10, respectively.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human , Triterpenes , Antiviral Agents/pharmacology , Humans , Influenza, Human/drug therapy , Oleanolic Acid/analogs & derivatives , Triterpenes/pharmacology
2.
Pharmacol Res ; 178: 106138, 2022 04.
Article in English | MEDLINE | ID: covidwho-1693034

ABSTRACT

Licorice (Glycyrrhiza glabra) is a well-known natural herb used to treat different ailments since ancient times. Glycyrrhizin (GL), which is the primary triterpenoid compound of licorice extract, has been known to have broad-spectrum pharmacological effects. GL is cleaved into glucuronide and the aglycone, glycyrrhetinic acid (GA), which exists in two stereoisomeric forms: 18α- and 18ß-GA. It is well documented that GL and GA have great potential as anti-inflammatory, anticancer, antiviral, anti-diabetic, antioxidant, and hepatoprotective agents. Studies undertaken during the coronavirus disease 2019 pandemic suggest that GL is effective at inhibiting the viral replication of severe acute respiratory syndrome coronavirus 2. The anticancer effects of GL and GA involve modulating various signaling pathways, such as the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B pathway, the mitogen-activated protein kinase, and the mammalian target of rapamycin/signal transducer and activator of transcription 3, which are mainly involved in regulating cancer cell death, oxidative stress, and inflammation. The potential of GL and GA in preventing cancer development and suppressing the growth and invasion of different cancer types has been reviewed in this paper. This review also provides molecular insights on the mechanism of action for the oncopreventive and oncotherapeutic effects of GL and its derivative, GA, which could help develop more specific forms of these agents for clinical use.


Subject(s)
Antineoplastic Agents , COVID-19 , Glycyrrhiza , Triterpenes , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Phytochemicals , Plant Extracts , Triterpenes/pharmacology , Triterpenes/therapeutic use
3.
Clin Nutr ESPEN ; 47: 414-417, 2022 02.
Article in English | MEDLINE | ID: covidwho-1591012

ABSTRACT

Ursolic acid (UA) is a pentacyclic terpenoid is usually found in the fruit peels and stem bark as secondary metabolites. UA has antiviral, antibacterial, and antiparasitic properties. UA has a wide spectrum of pharmacological activities against different infections. Because of the greatest antiviral and anti-inflammatory properties of UA, so it could be a plausible therapeutic herbal medicine in Covid-19 treatment. Covid-19 is a recent worldwide virulent disease pandemic due to severe acute respiratory coronavirus disease 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and exaggerated immune response by which acute lung injury (ALI) and/or acute respiratory distress syndrome might be developed in critical cases. UA may inhibit main protease of SARS-CoV-2, and inhibits the interface flanked by SARS-CoV-2 viral proteins and its entry point commonly recognized as angiotensin converting enzyme 2 (ACE2). In addition, UA attenuates SARS-CoV-2-induced inflammatory reactions and oxidative stress. Therefore, UA could avert SARS-CoV-2 infection from causing ALI. This opinion proposed that UA might be a potential candidate therapy against Covid-19 and can mitigate post-Covid-19 complications such as lung fibrosis. In this regards, forthcoming studies are reasonable to substantiate the therapeutic role of UA in Covid-19. However, taken into account that Covid-19 is yet to be investigating for further evaluations, therefore, clinical trials are recommended regarding use and dose of UA in Covid-19 treatment, as well as secondary effects.


Subject(s)
COVID-19 , Triterpenes , COVID-19/drug therapy , Humans , SARS-CoV-2 , Triterpenes/pharmacology
4.
J Adv Res ; 36: 201-210, 2022 02.
Article in English | MEDLINE | ID: covidwho-1536631

ABSTRACT

Introduction: The COVID-19 global epidemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a great public health emergency. Discovering antiviral drug candidates is urgent for the prevention and treatment of COVID-19. Objectives: This work aims to discover natural SARS-CoV-2 inhibitors from the traditional Chinese herbal medicine licorice. Methods: We screened 125 small molecules from Glycyrrhiza uralensis Fisch. (licorice, Gan-Cao) by virtual ligand screening targeting the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. Potential hit compounds were further evaluated by ELISA, SPR, luciferase assay, antiviral assay and pharmacokinetic study. Results: The triterpenoids licorice-saponin A3 (A3) and glycyrrhetinic acid (GA) could potently inhibit SARS-CoV-2 infection, with EC50 of 75 nM and 3.17 µM, respectively. Moreover, we reveal that A3 mainly targets the nsp7 protein, and GA binds to the spike protein RBD of SARS-CoV-2. Conclusion: In this work, we found GA and A3 from licorice potently inhibit SARS-CoV-2 infection by affecting entry and replication of the virus. Our findings indicate that these triterpenoids may contribute to the clinical efficacy of licorice for COVID-19 and could be promising candidates for antiviral drug development.


Subject(s)
COVID-19 , Glycyrrhiza , Triterpenes , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Triterpenes/pharmacology
5.
Int J Mol Sci ; 22(22)2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1534090

ABSTRACT

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.


Subject(s)
Antitubercular Agents/chemistry , Mycobacterium tuberculosis/drug effects , Triterpenes/chemistry , Tuberculosis/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , DNA-Directed RNA Polymerases/genetics , Drug Design , Drug Resistance, Bacterial/genetics , Humans , Molecular Docking Simulation , Molecular Structure , Mycobacterium tuberculosis/pathogenicity , Rifampin/pharmacology , Triterpenes/pharmacology , Tuberculosis/genetics , Tuberculosis/microbiology
6.
BMC Pulm Med ; 21(1): 371, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1526622

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a kind of chronic lung diseases with the characteristics of airway remodeling and airflow obstruction. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating hepatitis. However, whether MgIG can treat other diseases and its action mechanism is still obscure. In this study, we evaluated the anti-inflammatory effect of MgIG in rats with COPD and investigated the underlying mechanisms. METHODS: Rat model of COPD was constructed by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction. Rats were randomly divided into 5 groups: control group, COPD model group, salmeterol fluticasone comparator group, low dose of MgIG group, and high dose of MgIG group. Except for normal control group, the other four groups received sensitization treatment by cigarette smoking and endotracheal-atomization of endotoxin lipopolysaccharide to construct COPD rats model. After model established successfully, the COPD rats in each group received corresponding dose of endotracheal-atomized normal saline, salmeterol fluticasone, and MgIG every day prior to exposure of cigarette smoke from days 30 to 45. Normal control group were treated with normal saline. Finally, All rats were euthanatized. Pulmonary function was measured. Cells in bronchoalveolar lavage fluid were classified, inflammatory factors IL-6 and TNF-α were determined, histopathological analysis was performed by HE staining, and expression of NLRP3 and cleaved caspase-1 in the lung tissue was also determined by Western blotting. RESULTS: It showed that MgIG treatment (0.40 or 0.80 mg/kg/day) could recover the weight and the clinical symptoms of rats with COPD, accompanied with lung inflammation infiltration reduction, airway wall attenuation, bronchial mucus secretion reduction. Additionally, MgIG administration reduced inflammatory cells (white blood cells, neutrophils, lymphocytes and monocytes) accumulation in bronchoalveolar lavage fluid and decreased IL-6 and TNF-α production in the serum of COPD rats. Furthermore, MgIG treatment also reduced the expression level of NLRP3 and cleaved caspase-1. CONCLUSION: It indicate that MgIG might be an alternative for COPD treatment, and its mechanism of action might be related to the suppression of NLRP3 inflammasome.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Saponins/pharmacology , Triterpenes/pharmacology , Animals , China , Inflammation/prevention & control , Lung/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein , Pulmonary Disease, Chronic Obstructive/pathology , Rats , Rats, Wistar , Smoking
7.
Cell Rep ; 37(2): 109806, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1466094

ABSTRACT

Tactical disruption of protein synthesis is an attractive therapeutic strategy, with the first-in-class eIF4A-targeting compound zotatifin in clinical evaluation for cancer and COVID-19. The full cellular impact and mechanisms of these potent molecules are undefined at a proteomic level. Here, we report mass spectrometry analysis of translational reprogramming by rocaglates, cap-dependent initiation disruptors that include zotatifin. We find effects to be far more complex than simple "translational inhibition" as currently defined. Translatome analysis by TMT-pSILAC (tandem mass tag-pulse stable isotope labeling with amino acids in cell culture mass spectrometry) reveals myriad upregulated proteins that drive hitherto unrecognized cytotoxic mechanisms, including GEF-H1-mediated anti-survival RHOA/JNK activation. Surprisingly, these responses are not replicated by eIF4A silencing, indicating a broader translational adaptation than currently understood. Translation machinery analysis by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) identifies rocaglate-specific dependence on specific translation factors including eEF1ε1 that drive translatome remodeling. Our proteome-level interrogation reveals that the complete cellular response to these historical "translation inhibitors" is mediated by comprehensive translational landscape remodeling.


Subject(s)
Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Animals , Benzofurans/pharmacology , Cell Line, Tumor , Eukaryotic Initiation Factor-4A/drug effects , Eukaryotic Initiation Factor-4A/metabolism , Humans , Male , Mice , Mice, Inbred NOD , Primary Cell Culture , Protein Biosynthesis/physiology , Proteomics/methods , Ribosomes/metabolism , Transcriptome/drug effects , Transcriptome/genetics , Triterpenes/pharmacology
8.
Int J Mol Sci ; 22(19)2021 Oct 02.
Article in English | MEDLINE | ID: covidwho-1463709

ABSTRACT

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biological Products/pharmacology , Triterpenes/pharmacology , Angiogenesis Inhibitors , Antineoplastic Agents/chemistry , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Triterpenes/chemistry
9.
Arch Pharm (Weinheim) ; 354(11): e2100160, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1370365

ABSTRACT

Boswellic acids (BAs) have been shown to possess antiviral activity. Using bioinformatic methods, it was tested whether or not acetyl-11-keto-ß-boswellic acid (AKBA), 11-keto-ß-boswellic acid (KBA), ß-boswellic acid (BBA), and the phosphorylated active metabolite of Remdesivir® (RGS-P3) bind to functional proteins of SARS-CoV-2, that is, the replicase polyprotein P0DTD1, the spike glycoprotein P0DTC2, and the nucleoprotein P0DTC9. Using P0DTD1, AKBA and KBA showed micromolar binding affinity to the RNA-dependent RNA polymerase (RdRp) and to the main proteinase complex Mpro . Phosphorylated BAs even bond in the nanomolar range. Due to their positive and negative charges, BAs and RGS-P3 bond to corresponding negative and positive areas of the protein. BAs and RGS-P3 docked in the tunnel-like cavity of RdRp. BAs also docked into the elongated surface rim of viral Mpro . In both cases, binding occurred with active site amino acids in the lower micromolecular to upper nanomolar range. KBA, BBA, and RGS-P3 also bond to P0DTC2 and P0DTC9. The binding energies for BAs were in the range of -5.8 to -6.3 kcal/mol. RGS-P3 and BAs occluded the centrally located pore of the donut-like protein structure of P0DTC9 and, in the case of P0DTC2, RGS-P3 and BAs impacted the double-wing-like protein structure. The data of this bioinformatics study clearly show that BAs bind to three functional proteins of the SARS-CoV-2 virus responsible for adhesion and replication, as does RGS-P3, a drug on the market to treat this disease. The binding effectiveness of BAs can be increased through phosphate esterification. Whether or not BAs are druggable against the SARS-CoV-2 disease remains to be established.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/physiology , Triterpenes/pharmacology , Viral Proteins/physiology , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Binding Sites/physiology , Boswellia , COVID-19/drug therapy , COVID-19/virology , Computational Biology/methods , Humans , Molecular Docking Simulation , Nucleoproteins/metabolism , Polyproteins/metabolism , Prodrugs/pharmacology , Protein Binding/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Structure-Activity Relationship
10.
Int J Biol Macromol ; 187: 769-779, 2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1283357

ABSTRACT

Ganoderma lucidum (G. lucidum) polysaccharides and triterpenoids are the major bioactive compounds and have been used as traditional medicine for ancient times. Massive demands of G. lucidum have fascinated the researchers towards its application as functional food, nutraceutical and modern medicine owing to wide range of application in various diseases include immunomodulators, anticancer, antiviral, antioxidant, cardioprotective, hepatoprotective. G. lucidum polysaccharides exhibit immunomodulatory properties through boosting the action of antigen-presenting cells, mononuclear phagocyte system, along with humoral and cellular immunity. ß-Glucans isolated from G. lucidum are anticipated to produce an immune response through pathogen associated molecular patterns (PAMPs). ß-Glucans after binding with dectin-1 receptor present on different cells include macrophages, monocytes, dendritic cells and neutrophils produce signal transduction that lead to trigger the mitogen-activated protein kinases (MAPKs), T cells and Nuclear factor-κB (NF-κB) that refer to cytokines production and contributing to immune response. While triterpenoids produce antiviral effects through inhibiting various enzymes like neuraminidase, HIV-protease, DENV2 NS2B-NS3 protease and HSV multiplication. Polysaccharides and triterpenoids adjunct to other drugs exhibit potential action in prevention and treatment of various diseases. Immunomodulators and antiviral properties of this mushroom could be a potential source to overcome this current pandemic outbreak.


Subject(s)
Antiviral Agents/pharmacology , Immune System/drug effects , Reishi , Triterpenes/pharmacology , Virus Diseases/drug therapy , beta-Glucans/pharmacology , Animals , Antiviral Agents/isolation & purification , Host-Pathogen Interactions , Humans , Immune System/immunology , Immune System/metabolism , Molecular Structure , Reishi/chemistry , Signal Transduction , Structure-Activity Relationship , Triterpenes/isolation & purification , Virus Diseases/immunology , Virus Diseases/metabolism , Virus Diseases/virology , beta-Glucans/isolation & purification
11.
Exp Mol Med ; 53(5): 956-972, 2021 05.
Article in English | MEDLINE | ID: covidwho-1243283

ABSTRACT

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann-Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , SARS-CoV-2/drug effects , Saponins/pharmacology , Serine Endopeptidases/metabolism , Triterpenes/pharmacology , Virus Internalization/drug effects , Antiviral Agents/chemistry , COVID-19/metabolism , Cell Line , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Models, Molecular , Platycodon/chemistry , SARS-CoV-2/physiology , Saponins/chemistry , Triterpenes/chemistry
12.
Molecules ; 26(9)2021 May 01.
Article in English | MEDLINE | ID: covidwho-1224074

ABSTRACT

SARS CoV-2 pandemic is still considered a global health disaster, and newly emerged variants keep growing. A number of promising vaccines have been recently developed as a protective measure; however, cost-effective treatments are also of great importance to support this critical situation. Previously, betulinic acid has shown promising antiviral activity against SARS CoV via targeting its main protease. Herein, we investigated the inhibitory potential of this compound together with three other triterpene congeners (i.e., ursolic acid, maslinic acid, and betulin) derived from olive leaves against the viral main protease (Mpro) of the currently widespread SARS CoV-2. Interestingly, betulinic, ursolic, and maslinic acids showed significant inhibitory activity (IC50 = 3.22-14.55 µM), while betulin was far less active (IC50 = 89.67 µM). A comprehensive in-silico analysis (i.e., ensemble docking, molecular dynamic simulation, and binding-free energy calculation) was then performed to describe the binding mode of these compounds with the enzyme catalytic active site and determine the main essential structural features required for their inhibitory activity. Results presented in this communication indicated that this class of compounds could be considered as a promising lead scaffold for developing cost-effective anti-SARS CoV-2 therapeutics.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Triterpenes/pharmacology , Antiviral Agents/chemistry , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Olea/chemistry , Pentacyclic Triterpenes/chemistry , Pentacyclic Triterpenes/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Triterpenes/chemistry
13.
Eur J Med Chem ; 215: 113242, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1086914

ABSTRACT

Currently, SARS-CoV-2 virus is an emerging pathogen that has posed a serious threat to public health worldwide. However, no agents have been approved to treat SARS-CoV-2 infections to date, underscoring the great need for effective and practical therapies for SARS-CoV-2 outbreaks. We reported that a focused screen of OA saponins identified 3-O-ß-chacotriosyl OA benzyl ester 2 as a novel small molecule inhibitor of SARS-CoV-2 virus entry, via binding to SARS-CoV-2 glycoprotein (S). We performed structure-activity relationship profiling of 2 and discovered C-17-COOH of OA was an important modification site that improved both inhibitor potency toward SARS-CoV-2 and selectivity index. Then optimization from hit to lead resulted in a potent fusion inhibitor 12f displaying strong inhibition against infectious SARS-CoV-2 with an IC50 value of 0.97 µM in vitro. Mechanism studies confirmed that inhibition of SARS-CoV-2 viral entry of 12f was mediated by the direct interaction with SARS-CoV-2 S2 subunit to block membrane fusion. These 3-O-ß-chacotriosyl OA amide saponins are suitable for further optimization as SARS-CoV-2 entry inhibitors with the potential to be developed as therapeutic agents for the treatment of SARS-CoV-2 virus infections.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Saponins/pharmacology , Triterpenes/pharmacology , Virus Internalization/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Chlorocebus aethiops , Drug Discovery , HEK293 Cells , Humans , Microbial Sensitivity Tests , Molecular Structure , Protein Binding , Protein Subunits/metabolism , Saponins/chemical synthesis , Saponins/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , Triterpenes/chemical synthesis , Triterpenes/metabolism , Vero Cells
14.
Molecules ; 26(1)2020 Dec 24.
Article in English | MEDLINE | ID: covidwho-1044927

ABSTRACT

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, µM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 µM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Protein Interaction Domains and Motifs/drug effects , SARS-CoV-2/metabolism , Surface Plasmon Resonance/methods , Triterpenes/pharmacology , Viral Proteins/metabolism , HEK293 Cells , Humans , Protein Binding
15.
Biosci Rep ; 41(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1043444

ABSTRACT

OBJECTIVE: ´Three formulas and three medicines,' namely, Jinhua Qinggan Granule, Lianhua Qingwen Capsule, Xuebijing Injection, Qingfei Paidu Decoction, HuaShi BaiDu Formula, and XuanFei BaiDu Granule, were proven to be effective for coronavirus disease 2019 (COVID-19) treatment. The present study aimed to identify the active chemical constituents of this traditional Chinese medicine (TCM) and investigate their mechanisms through interleukin-6 (IL-6) integrating network pharmacological approaches. METHODS: We collected the compounds from all herbal ingredients of the previously mentioned TCM, but those that could down-regulate IL-6 were screened through the network pharmacology approach. Then, we modeled molecular docking to evaluate the binding affinity between compounds and IL-6. Furthermore, we analyzed the biological processes and pathways of compounds. Finally, we screened out the core genes of compounds through the construction of the protein-protein interaction network and the excavation of gene clusters of compounds. RESULTS: The network pharmacology research showed that TCM could decrease IL-6 using several compounds, such as quercetin, ursolic acid, luteolin, and rutin. Molecular docking results showed that the molecular binding affinity with IL-6 of all compounds except γ-aminobutyric acid was < -5.0 kJ/mol, indicating the potential of numerous active compounds in TCM to directly interact with IL-6, leading to an anti-inflammation effect. Finally, Cytoscape 3.7.2 was used to topologize the biological processes and pathways of compounds, revealing potential mechanisms for COVID-19 treatment. CONCLUSION: These results indicated the positive effect of TCM on the prevention and rehabilitation of COVID-19 in at-risk people. Quercetin, ursolic acid, luteolin, and rutin could inhibit COVID-19 by down-regulating IL-6.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Interleukin-6/immunology , Anti-Inflammatory Agents/chemistry , COVID-19/immunology , Drug Discovery , Drugs, Chinese Herbal/chemistry , Humans , Interleukin-6/antagonists & inhibitors , Luteolin/analysis , Luteolin/pharmacology , Medicine, Chinese Traditional , Molecular Docking Simulation , Protein Interaction Maps/drug effects , Quercetin/analysis , Quercetin/pharmacology , Rutin/analysis , Rutin/pharmacology , Triterpenes/analysis , Triterpenes/pharmacology
16.
Int J Mol Sci ; 21(23)2020 Dec 04.
Article in English | MEDLINE | ID: covidwho-965309

ABSTRACT

We describe the potential anti coronavirus disease 2019 (COVID-19) action of the methide quinone inhibitor, celastrol. The related methide quinone dexamethasone is, so far, among COVID-19 medications perhaps the most effective drug for patients with severe symptoms. We observe a parallel redox biology behavior between the antioxidant action of celastrol when scavenging the superoxide radical, and the adduct formation of celastrol with the main COVID-19 protease. The related molecular mechanism is envisioned using molecular mechanics and dynamics calculations. It proposes a covalent bond between the S(Cys145) amino acid thiolate and the celastrol A ring, assisted by proton transfers by His164 and His41 amino acids, and a π interaction from Met49 to the celastrol B ring. Specifically, celastrol possesses two moieties that are able to independently scavenge the superoxide radical: the carboxylic framework located at ring E, and the methide-quinone ring A. The latter captures the superoxide electron, releasing molecular oxygen, and is the feature of interest that correlates with the mechanism of COVID-19 inhibition. This unusual scavenging of the superoxide radical is described using density functional theory (DFT) methods, and is supported experimentally by cyclic voltammetry and X-ray diffraction.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Free Radical Scavengers/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Tripterygium/chemistry , Triterpenes/pharmacology , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Free Radical Scavengers/chemistry , Humans , Models, Molecular , Pentacyclic Triterpenes , Plant Roots/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , Superoxides/metabolism , Triterpenes/chemistry
17.
Biomolecules ; 10(11)2020 11 02.
Article in English | MEDLINE | ID: covidwho-921178

ABSTRACT

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.


Subject(s)
Antiviral Agents/pharmacology , Triterpenes/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Betacoronavirus/physiology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Plants/chemistry , SARS-CoV-2 , Triterpenes/chemistry , Triterpenes/metabolism
18.
Phytother Res ; 34(10): 2471-2492, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-864251

ABSTRACT

Several corona viral infections have created serious threats in the last couple of decades claiming the death of thousands of human beings. Recently, corona viral epidemic raised the issue of developing effective antiviral agents at the earliest to prevent further losses. Natural products have always played a crucial role in drug development process against various diseases, which resulted in screening of such agents to combat emergent mutants of corona virus. This review focuses on those natural compounds that showed promising results against corona viruses. Although inhibition of viral replication is often considered as a general mechanism for antiviral activity of most of the natural products, studies have shown that some natural products can interact with key viral proteins that are associated with virulence. In this context, some of the natural products have antiviral activity in the nanomolar concentration (e.g., lycorine, homoharringtonine, silvestrol, ouabain, tylophorine, and 7-methoxycryptopleurine) and could be leads for further drug development on their own or as a template for drug design. In addition, a good number of natural products with anti-corona virus activity are the major constituents of some common dietary supplements, which can be exploited to improve the immunity of the general population in certain epidemics.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/virology , Coronavirus/drug effects , Plant Extracts/pharmacology , Alkaloids/pharmacology , Animals , Biological Products/pharmacology , Coronavirus/metabolism , Coronavirus/pathogenicity , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Drug Development , Humans , Indolizines/pharmacology , Ouabain/pharmacology , Phenanthrenes/pharmacology , Quinolizines/pharmacology , Triterpenes/pharmacology , Viral Proteins/metabolism , Virus Replication/drug effects
19.
Biomolecules ; 10(8)2020 08 05.
Article in English | MEDLINE | ID: covidwho-696191

ABSTRACT

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3-5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid-spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3',3'-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 µM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.


Subject(s)
Anti-HIV Agents/chemical synthesis , Molecular Docking Simulation , Triterpenes/chemistry , gag Gene Products, Human Immunodeficiency Virus/metabolism , Anti-HIV Agents/pharmacology , Binding Sites , Phosphates/chemistry , Protein Binding , Succinates/chemistry , Succinates/pharmacology , Triterpenes/pharmacology , gag Gene Products, Human Immunodeficiency Virus/chemistry
20.
Comput Biol Med ; 124: 103936, 2020 09.
Article in English | MEDLINE | ID: covidwho-679767

ABSTRACT

Virtual screening of phytochemicals was performed through molecular docking, simulations, in silico ADMET and drug-likeness prediction to identify the potential hits that can inhibit the effects of SARS-CoV-2. Considering the published literature on medicinal importance, 154 phytochemicals with analogous structure from limonoids and triterpenoids were selected to search potential inhibitors for the five therapeutic protein targets of SARS-CoV-2, i.e., 3CLpro (main protease), PLpro (papain-like protease), SGp-RBD (spike glycoprotein-receptor binding domain), RdRp (RNA dependent RNA polymerase) and ACE2 (angiotensin-converting enzyme 2). The in silico computational results revealed that the phytochemicals such as glycyrrhizic acid, limonin, 7-deacetyl-7-benzoylgedunin, maslinic acid, corosolic acid, obacunone and ursolic acid were found to be effective against the target proteins of SARS-CoV-2. The protein-ligand interaction study revealed that these phytochemicals bind with the amino acid residues at the active site of the target proteins. Therefore, the core structure of these potential hits can be used for further lead optimization to design drugs for SARS-CoV-2. Also, the medicinal plants containing these phytochemicals like licorice, neem, tulsi, citrus and olives can be used to formulate suitable therapeutic approaches in traditional medicines.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Limonins/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Triterpenes/pharmacology , Angiotensin-Converting Enzyme 2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , COVID-19 , Computational Biology , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase , Drug Evaluation, Preclinical , Host Microbial Interactions/drug effects , Humans , Limonins/chemistry , Limonins/pharmacokinetics , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/drug effects , Phytochemicals/chemistry , Phytochemicals/pharmacokinetics , Phytochemicals/pharmacology , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Triterpenes/chemistry , Triterpenes/pharmacokinetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , Viral Proteins/chemistry , Viral Proteins/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL