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1.
Molecules ; 27(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613911

ABSTRACT

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 µM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , SARS-CoV-2/drug effects , Virus Replication , Animals , Antiviral Agents/chemical synthesis , COVID-19/virology , Chlorocebus aethiops , HIV Infections/virology , HeLa Cells , Humans , In Vitro Techniques , Vero Cells
2.
Molecules ; 26(20)2021 Oct 09.
Article in English | MEDLINE | ID: covidwho-1463773

ABSTRACT

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.


Subject(s)
Glycyrrhizic Acid/chemistry , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Glycyrrhizic Acid/metabolism , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization/drug effects
3.
Molecules ; 26(19)2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1463772

ABSTRACT

The naturally occurring saponins exhibit remarkable interfacial activity and also possess many biological activities linking to human health benefits, which make them particularly attractive as bifunctional building blocks for formulation of colloidal multiphase food systems. This review focuses on two commonly used food-grade saponins, Quillaja saponins (QS) and glycyrrhizic acid (GA), with the aim of clarifying the relationship between the structural features of saponin molecules and their subsequent self-assembly and interfacial properties. The recent applications of these two saponins in various colloidal multiphase systems, including liquid emulsions, gel emulsions, aqueous foams and complex emulsion foams, are then discussed. A particular emphasis is on the unique use of GA and GA nanofibrils as sole stabilizers for fabricating various multiphase food systems with many advanced qualities including simplicity, ultrastability, stimulability, structural viscoelasticity and processability. These natural saponin and saponin-based colloids are expected to be used as sustainable, plant-based ingredients for designing future foods, cosmetics and pharmaceuticals.


Subject(s)
Glycyrrhizic Acid/chemistry , Plants/chemistry , Quillaja Saponins/chemistry , Colloids/chemistry , Cosmetics/chemistry , Food Technology , Molecular Structure , Phytochemicals/chemistry
4.
J Mol Model ; 27(7): 206, 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1384472

ABSTRACT

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , Antiviral Agents/chemistry , Binding Sites , COVID-19/enzymology , COVID-19/virology , Drug Discovery , Drug Repositioning , Glycyrrhizic Acid/analogs & derivatives , Glycyrrhizic Acid/chemistry , Host-Pathogen Interactions , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
5.
ACS Appl Mater Interfaces ; 13(18): 20995-21006, 2021 May 12.
Article in English | MEDLINE | ID: covidwho-1209173

ABSTRACT

COVID-19 has been diffusely pandemic around the world, characterized by massive morbidity and mortality. One of the remarkable threats associated with mortality may be the uncontrolled inflammatory processes, which were induced by SARS-CoV-2 in infected patients. As there are no specific drugs, exploiting safe and effective treatment strategies is an instant requirement to dwindle viral damage and relieve extreme inflammation simultaneously. Here, highly biocompatible glycyrrhizic acid (GA) nanoparticles (GANPs) were synthesized based on GA. In vitro investigations revealed that GANPs inhibit the proliferation of the murine coronavirus MHV-A59 and reduce proinflammatory cytokine production caused by MHV-A59 or the N protein of SARS-CoV-2. In an MHV-A59-induced surrogate mouse model of COVID-19, GANPs specifically target areas with severe inflammation, such as the lungs, which appeared to improve the accumulation of GANPs and enhance the effectiveness of the treatment. Further, GANPs also exert antiviral and anti-inflammatory effects, relieving organ damage and conferring a significant survival advantage to infected mice. Such a novel therapeutic agent can be readily manufactured into feasible treatment for COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Glycyrrhizic Acid/therapeutic use , Inflammation/drug therapy , Nanoparticles/therapeutic use , Virus Diseases/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Antioxidants/therapeutic use , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus Nucleocapsid Proteins/pharmacology , Cytokines/metabolism , Female , Glycyrrhizic Acid/chemistry , Humans , Liver/pathology , Lung/pathology , Mice , Mice, Inbred BALB C , Murine hepatitis virus/drug effects , Nanoparticles/chemistry , Phosphoproteins/pharmacology , RAW 264.7 Cells , SARS-CoV-2/chemistry , THP-1 Cells , Viral Load/drug effects , Virus Diseases/pathology , Virus Replication/drug effects
6.
Int J Mol Sci ; 22(6)2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1125145

ABSTRACT

In order to treat Coronavirus Disease 2019 (COVID-19), we predicted and implemented a drug delivery system (DDS) that can provide stable drug delivery through a computational approach including a clustering algorithm and the Schrödinger software. Six carrier candidates were derived by the proposed method that could find molecules meeting the predefined conditions using the molecular structure and its functional group positional information. Then, just one compound named glycyrrhizin was selected as a candidate for drug delivery through the Schrödinger software. Using glycyrrhizin, nafamostat mesilate (NM), which is known for its efficacy, was converted into micelle nanoparticles (NPs) to improve drug stability and to effectively treat COVID-19. The spherical particle morphology was confirmed by transmission electron microscopy (TEM), and the particle size and stability of 300-400 nm were evaluated by measuring DLSand the zeta potential. The loading of NM was confirmed to be more than 90% efficient using the UV spectrum.


Subject(s)
COVID-19/drug therapy , Computational Biology/methods , Drug Delivery Systems/methods , A549 Cells , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Benzamidines/chemistry , Benzamidines/therapeutic use , Cell Survival/drug effects , Cluster Analysis , Computer Simulation , Databases, Pharmaceutical , Drug Carriers/chemistry , Drug Repositioning , Drug Stability , Glycyrrhizic Acid/chemistry , Glycyrrhizic Acid/therapeutic use , Guanidines/chemistry , Guanidines/therapeutic use , Humans , Hydrophobic and Hydrophilic Interactions , Micelles , Microscopy, Electron, Transmission , Molecular Structure , Nanoparticles/chemistry , Particle Size
7.
J Phys Chem Lett ; 11(22): 9659-9668, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-899848

ABSTRACT

SARS-CoV-2 is the cause of the ongoing Coronavirus disease 19 (COVID-19) pandemic around the world causing pneumonia and lower respiratory tract infections. In understanding the SARS-CoV-2 pathogenicity and mechanism of action, it is essential to depict the full repertoire of expressed viral proteins. The recent biological studies have highlighted the leader protein Nsp1 of SARS-CoV-2 importance in shutting down the host protein production. Besides, it still enigmatic how Nsp1 regulates for translation. Here we report the novel structure of Nsp1 from SARS-CoV-2 in complex with the SL1 region of 5'UTR of SARS-CoV-2, and its factual interaction is corroborated with enzyme kinetics and experimental binding affinity studies. The studies also address how leader protein Nsp1 of SARS-CoV-2 recognizes its self RNA toward translational regulation by further recruitment of the 40S ribosome. With the aid of molecular dynamics and simulations, we also demonstrated the real-time stability and functional dynamics of the Nsp1/SL1 complex. The studies also report the potential inhibitors and their mode of action to block viral protein/RNA complex formation. This enhance our understanding of the mechanism of the first viral protein Nsp1 synthesized in the human cell to regulate the translation of self and host. Understanding the structure and mechanism of SARS-CoV-2 Nsp1 and its interplay with the viral RNA and ribosome will open the arena for exploring the development of live attenuated vaccines and effective therapeutic targets for this disease.


Subject(s)
5' Untranslated Regions , RNA, Viral/metabolism , SARS-CoV-2/chemistry , Viral Nonstructural Proteins/metabolism , COVID-19 Vaccines , Depsides/chemistry , Depsides/metabolism , Glycyrrhizic Acid/chemistry , Glycyrrhizic Acid/metabolism , Lactones/chemistry , Lactones/metabolism , Molecular Dynamics Simulation , Pregnatrienes/chemistry , Pregnatrienes/metabolism , Protein Binding/drug effects , RNA, Viral/chemistry , Ribosome Subunits, Small, Eukaryotic/chemistry , Ribosome Subunits, Small, Eukaryotic/metabolism , SARS-CoV-2/pathogenicity , Salicylates/chemistry , Salicylates/metabolism , Viral Nonstructural Proteins/chemistry , Virulence
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