scholarly journals Preventing the Interaction between Coronaviruses Spike Protein and Angiotensin I Converting Enzyme 2: An In Silico Mechanistic Case Study on Emodin as a Potential Model Compound

2020 ◽  
Vol 10 (18) ◽  
pp. 6358
Author(s):  
Luca Dellafiora ◽  
Jean Lou C M Dorne ◽  
Gianni Galaverna ◽  
Chiara Dall’Asta
Keyword(s):  
Adverse Effects ◽  
Antiviral Activity ◽  
Model Compound ◽  
Biological Activities ◽  
Mechanistic Explanation ◽  
Host Cells ◽  
Spike Protein ◽  
Docking Simulations ◽  
Functional Conservation ◽  
Beneficial Effects

Emodin, a widespread natural anthraquinone, has many biological activities including health-protective and adverse effects. Amongst beneficial effects, potential antiviral activity against coronavirus responsible for the severe acute respiratory syndrome outbreak in 2002–2003 has been described associated with the inhibition of the host cells target receptors recognition by the viral Spike protein. However, the inhibition mechanisms have not been fully characterized, hindering the rational use of emodin as a model compound to develop more effective analogues. This work investigates emodin interaction with the Spike protein to provide a mechanistic explanation of such inhibition. A 3D molecular modeling approach consisting of docking simulations, pharmacophoric analysis and molecular dynamics was used. The plausible mechanism is described as an interaction of emodin at the protein–protein interface which destabilizes the viral protein-target receptor complex. This analysis has been extended to the Spike protein of the coronavirus responsible for the current pandemic hypothesizing emodin’s functional conservation. This solid knowledge-based foothold provides a possible mechanistic rationale of the antiviral activity of emodin as a future basis for the potential development of efficient antiviral cognate compounds. Data gaps and future work on emodin-related adverse effects in parallel to its antiviral pharmacology are explored.

scholarly journals The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2, in vitro

2021 ◽  
Author(s):  
Riho Tateyama-Makino ◽  
Mari Abe-Yutori ◽  
Taku Iwamoto ◽  
Kota Tsutsumi ◽  
Motonori Tsuji ◽  
...  
Keyword(s):  
Serine Protease ◽  
Protease Activity ◽  
Oral Care ◽  
Sodium Dodecyl ◽  
Host Cells ◽  
Spike Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inhibitory Effects ◽  
Docking Simulations

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the viral spike protein is cleaved by transmembrane protease serine 2 (TMPRSS2) after binding to the host angiotensin-converting enzyme 2 (ACE2). Since ACE2 and TMPRSS2 are expressed in the mucosa of the tongue and gingiva, the oral cavity seems like it is an entry point for SARS-CoV-2. Daily oral care using mouthwash seems to play an important role in preventing SARS-CoV-2 infection. However, the relationship between daily oral care and the mechanisms of virus entry into host cells is unclear. In this study, we evaluated the inhibitory effects of ingredients that are generally contained in toothpaste and mouthwash on the interaction between the spike protein and ACE2 and on the serine protease activity of TMPRSS2 using an enzyme-linked immunosorbent assay and in vitro enzyme assay, respectively. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to the inhibitor-binding site of ACE2. In addition, tranexamic acid and 6-aminohexanoic acid, which act as serine protease inhibitors, exerted inhibitory effects on TMPRSS2 protease activity. Further experimental and clinical studies are needed to further elucidate these mechanisms. Our findings support the possibility that toothpaste and mouthwash contain ingredients that inhibit SARS-CoV-2 infection.

scholarly journals A New Monoclonal Antibody, mAb 4A12, Identifies a Role for the Glycosaminoglycan (GAG) Binding Domain of RANTES in the Antiviral Effect against HIV-1 and Intracellular Ca2+ Signaling

1998 ◽  
Vol 188 (10) ◽  
pp. 1917-1927 ◽  
Author(s):  
Jennifer M. Burns ◽  
Robert C. Gallo ◽  
Anthony L. DeVico ◽  
George K. Lewis
Keyword(s):  
Monoclonal Antibody ◽  
Antiviral Activity ◽  
Transmembrane Domain ◽  
Biological Activities ◽  
Binding Domain ◽  
Host Cells ◽  
Cell Surfaces ◽  
Susceptible Host ◽  
Hiv 1 ◽  
Helical Region

The β-chemokine RANTES (regulated on activation, normal T cell expressed and secreted) suppresses the infection of susceptible host cells by macrophage tropic strains of HIV-1. This effect is attributed to interactions of this chemokine with a 7-transmembrane domain receptor, CCR5, that is required for virus–cell fusion and entry. Here we identify domains of RANTES that contribute to its biological activities through structure–function studies using a new monoclonal antibody, mAb 4A12, isolated from mice immunized with recombinant human RANTES. This monoclonal antibody (mAb) blocked the antiviral activity of RANTES in infectivity assays with HIV-1Bal, and inhibited the mobilization of intracellular Ca2+ elicited by RANTES, yet recognized this chemokine bound to cell surfaces. Epitope mapping using limited proteolysis, reversed phase high-performance liquid chromatography, and mass spectrometry suggest that residues 55–66 of RANTES, which include the COOH-terminal α-helical region implicated as the glycosaminoglycan (GAG) binding domain, overlap the determinant recognized by mAb 4A12. This is supported by affinity chromatography studies, which showed that RANTES could be eluted specifically by heparin from a mAb 4A12 immunoaffinity matrix. Removal of cell surface GAGs by enzymatic digestion greatly reduced the ability of mAb 4A12 to detect RANTES passively bound on cell surfaces and abrogated the ability of RANTES to elicit an intracellular Ca2+ signal. Taken together, these studies demonstrate that the COOH-terminal α-helical region of RANTES plays a key role in GAG-binding, antiviral activity, and intracellular Ca2+ signaling and support a model in which GAGs play a key role in the biological activities of this chemokine.

scholarly journals The inhibitory effects of toothpaste and mouthwash ingredients on the interaction between the SARS-CoV-2 spike protein and ACE2, and the protease activity of TMPRSS2 in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257705
Author(s):  
Riho Tateyama-Makino ◽  
Mari Abe-Yutori ◽  
Taku Iwamoto ◽  
Kota Tsutsumi ◽  
Motonori Tsuji ◽  
...  
Keyword(s):  
Protease Activity ◽  
Sodium Dodecyl ◽  
Host Cells ◽  
Spike Protein ◽  
Inhibitory Effects ◽  
Inhibitor Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Docking Simulations ◽  
Gingival Mucosa

SARS-CoV-2 enters host cells when the viral spike protein is cleaved by transmembrane protease serine 2 (TMPRSS2) after binding to the host angiotensin-converting enzyme 2 (ACE2). Since ACE2 and TMPRSS2 are expressed in the tongue and gingival mucosa, the oral cavity is a potential entry point for SARS-CoV-2. This study evaluated the inhibitory effects of general ingredients of toothpastes and mouthwashes on the spike protein-ACE2 interaction and the TMPRSS2 protease activity using an in vitro assay. Both assays detected inhibitory effects of sodium tetradecene sulfonate, sodium N-lauroyl-N-methyltaurate, sodium N-lauroylsarcosinate, sodium dodecyl sulfate, and copper gluconate. Molecular docking simulations suggested that these ingredients could bind to inhibitor-binding site of ACE2. Furthermore, tranexamic acid exerted inhibitory effects on TMPRSS2 protease activity. Our findings suggest that these toothpaste and mouthwash ingredients could help prevent SARS-CoV-2 infection.

scholarly journals Interference of Polydatin/Resveratrol in the ACE2:Spike Recognition during COVID-19 Infection. A Focus on Their Potential Mechanism of Action through Computational and Biochemical Assays

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1048
Author(s):  
Fulvio Perrella ◽  
Federico Coppola ◽  
Alessio Petrone ◽  
Chiara Platella ◽  
Daniela Montesarchio ◽  
...  
Keyword(s):  
Biological Activities ◽  
Cell Types ◽  
Host Cells ◽  
Respiratory Epithelial Cells ◽  
Docking Simulations ◽  
Biochemical Assays ◽  
Main Host ◽  
Multiple Cell ◽  
Dose Response Effect ◽  
Respiratory Epithelial

In the search for new therapeutic strategies to contrast SARS-CoV-2, we here studied the interaction of polydatin (PD) and resveratrol (RESV)—two natural stilbene polyphenols with manifold, well known biological activities—with Spike, the viral protein essential for virus entry into host cells, and ACE2, the angiotensin-converting enzyme present on the surface of multiple cell types (including respiratory epithelial cells) which is the main host receptor for Spike binding. Molecular Docking simulations evidenced that both compounds can bind Spike, ACE2 and the ACE2:Spike complex with good affinity, although the interaction of PD appears stronger than that of RESV on all the investigated targets. Preliminary biochemical assays revealed a significant inhibitory activity of the ACE2:Spike recognition with a dose-response effect only in the case of PD.

α-Glucosidase Inhibition, Antioxidant and Docking Studies of Hydroxycoumarins and their Mono and Bis O-alkylated/acetylated Analogs

2018 ◽  
Vol 15 (2) ◽  
pp. 127-135 ◽  
Author(s):  
Parvesh Singh ◽  
Nomandla Ngcoya ◽  
Ramgopal Mopuri ◽  
Nagaraju Kerru ◽  
Neha Manhas ◽  
...  
Keyword(s):  
In Silico ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Catalytic Site ◽  
Docking Simulations ◽  
In Silico Docking ◽  
Anti Oxidant

Background: Diabetes Mellitus (DM) is a complex metabolic disease illustrated by abnormally high levels of plasma glucose or hyperglycaemia. Accordingly, several α-glucosidase inhibitors have been developed for the treatment of diabetes and other degenerative disorders. While, a coumarin ring has the privilege to represent numerous natural and synthetic compounds with a wide spectrum of biological activities e.g. anti-cancer, anti-HIV, anti-viral, anti-malarial, anti-microbial, anti-convulsant, anti-hypertensive properties. Besides this, coumarins have also shown potential to inhibit α-glucosidase leading to a generation of new promising antidiabetic agents. However, the testing of O-substituted coumarins for α-glucosidase inhibition has evaded the attention of medicinal chemists. Methods: For O-alkylation/acetylation reactions, the hydroxyl coumarins (A-B) initially activated by K2CO3 in dry DMF were reacted with variedly substituted haloalkanes at room temperature under nitrogen. The synthesized compounds were tested for their α-glucosidase (from Saccharomyces cerevisiae) inhibitory activity and anti-oxidant activity using DPPH radical scavenging activity. In silico docking simulations were conducted using CDocker module in DS (Accelrys) to explore the binding modes of the representative compounds in the catalytic site of α-glucosidase. Results: All the coumarin analogues (A1, B1, A2-A10, B2-B8) including their precursors (A-B) were evaluated for their in vitro α-glucosidase inhibition using acarbose as a standard inhibitor. All the mono O-alkylated coumarins (except A1) showed significant (p <0.05) α-glucosidase inhibition relative to the hydroxyl coumarin (A) with IC50 values ranging between 11.084±0.117 to 145.24± 29.22 µg/mL. Compound 7-(benzyloxy)-4, 5-dimethyl-2H-chromen-2-one (A9) bearing a benzyl group (Ph-CH2-) at position 7 showed a remarkable (p <0.05) increase in the activity (IC50 = 11.084±0.117 µg/mL), almost four-fold more than acarbose (IC50 = 40.578±5.999 µg/mL). The introduction of –NO2 group dramatically improved the anti-oxidant activity of coumarin, while the O-alkylation/acetylation decreased the activity. Conclusion: The present study describes the synthesis of functionalized coumarins and their evaluation for α-glucosidase inhibition and antioxidant activity under in vitro conditions. Based on IC50 data, the mono O-alkylated coumarins were observed to be stronger inhibitors of α-glucosidase with respect to their bis O-alkylated analogues. Coumarin (A9) bearing O-benzyloxy group displayed the strongest α-glucosidase inhibition, even higher than the standard inhibitor acarbose. The coumarin (A10) bearing –NO2 group showed the highest anti-oxidant activity amongst the synthesized compounds, almost comparable to the ascorbic acid. Finally, in silico docking simulations revealed the role of hydrogen bonding and hydrophobic forces in locking the compounds in catalytic site of α-glucosidase.

Thymol Chemistry: A Medicinal Toolbox

2019 ◽  
Vol 15 (5) ◽  
pp. 454-474 ◽  
Author(s):  
Jyoti ◽  
Divya Dheer ◽  
Davinder Singh ◽  
Gulshan Kumar ◽  
Manvika Karnatak ◽  
...  
Keyword(s):  
Web Of Science ◽  
Biological Activities ◽  
Controlled Clinical Trials ◽  
Food Preservative ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Trachyspermum Ammi ◽  
Randomised Controlled ◽  
Human Infections ◽  
Potential Use

Background: Thymol is a natural phenolic monoterpenoid widely used in pharmaceutical and food preservative applications. Thymol isomeric with carvacrol, extracted primarily from Thymus species (Trachyspermum ammi) and other plants sources such as Baccharisgrise bachii and Centipeda minima, has ethnopharmacological characteristics. <p></p> Methods: This review was prepared by analyzing articles published on thymol moiety in last decade and selected from Science Direct, Scopus, Pub Med, Web of Science and SciFinder. The selected articles are classified and gives brief introduction about thymol and its isolation, illustrates its natural as well as synthetic sources, and also therapeutic benefits of thymol worldwide <p></p> Results: Thymol has been covering different endeavors such as antimicrobial, antioxidant, antiinflammatory, antibacterial, antifungal, antidiarrhoeal, anthelmintic, analgesic, digestive, abortifacient, antihypertensive, spermicidal, depigmenting, antileishmanial, anticholinesterase, insecticidal and many others. This phenolic compound is among the essential scaffolds for medicinal chemists to synthesize more bio-active molecules by further derivatization of the thymol moiety. <p></p> Conclusion: Thymol is an interesting scaffold due to its different activities and derivatization of thymol is proved to enhance its biological activities. However, more robust, randomised, controlled clinical trials would be desirable with well-characterised thymol preparations to corroborate its beneficial effects in diseased patients. Moreover, in view of the potential use of thymol and thymol-rich essential oils in the treatment of human infections, comprehensive studies on chronic and acute toxicity and also teratogenicity are to be recommended.

Preparation, spectral properties and biological activities of 5-bromo-6-methyl-2'-deoxyuridine and 5-iodo-6-methyl-2'-deoxyuridine

1980 ◽  
Vol 45 (8) ◽  
pp. 2364-2370 ◽  
Author(s):  
Antonín Holý ◽  
Erik De Clercq
Keyword(s):  
Antiviral Activity ◽  
Spectral Properties ◽  
De Novo ◽  
Biological Activities ◽  
Rabbit Kidney ◽  
Kidney Cells ◽  
Cd Spectra ◽  
Methyl Derivatives ◽  
Primary Rabbit

Reaction of 3',5'-di-O-benzoyl-6-methyl-2'-deoxyuridine (IIa) with elementary bromine or iodine afforded 5-halogeno derivatives IIc and IId which on methanolysis gave 5-bromo-6-methyl-2'-deoxyurine (Ic) and 5-iodo-6-methyl-2'-deoxyurine (Id), respectively. The CD spectra of Ic, Id and 6-methyl-2'-deoxyuridine (Ia) are compared and discussed with regard to determination of the nucleoside conformation. Unlike 5-bromo- and 5-iodo-2'-deoxyuridine, the 6-methyl derivatives Ic and Id exhibit neither antibacterial nor antiviral activity. Nor do they exert any antimetabolic effect on the de novo DNA synthesis in primary rabbit kidney cells.

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

scholarly journals Pinus Species as Prospective Reserves of Bioactive Compounds with Potential Use in Functional Food—Current State of Knowledge

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1306
Author(s):  
Marcin Dziedziński ◽  
Joanna Kobus-Cisowska ◽  
Barbara Stachowiak
Keyword(s):  
Human Health ◽  
Bioactive Compounds ◽  
Functional Food ◽  
Biological Activities ◽  
Food Ingredients ◽  
Beneficial Effects ◽  
Pine Tree ◽  
Pine Trees ◽  
Health Promoting ◽  
Few Data

The pine (Pinus L.) is the largest and most heteromorphic plant genus of the pine family (Pinaceae Lindl.), which grows almost exclusively in the northern hemisphere. The demand for plant-based remedies, supplements and functional food is growing worldwide. Although pine-based products are widely available in many parts of the world, they are almost absent as food ingredients. The literature shows the beneficial effects of pine preparations on human health. Despite the wide geographical distribution of pine trees in the natural environment, there are very few data in the literature on the widespread use of pine in food technology. This study aims to present, characterise and evaluate the content of phytochemicals in pine trees, including shoots, bark and conifer needles, as well as to summarise the available data on their health-promoting and functional properties, and the potential of their use in food and the pharmaceutical industry to support health. Various species of pine tree contain different compositions of bioactive compounds. Regardless of the solvent, method, pine species and plant part used, all pine extracts contain a high number of polyphenols. Pine tree extracts exhibit several described biological activities that may be beneficial to human health. The available examples of the application of pine elements in food are promising. The reuse of residual pine elements is still limited compared to its potential. In this case, it is necessary to conduct more research to find and develop new products and applications of pine residues and by-products.

scholarly journals Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 346
Author(s):  
Caitlin W. Lehman ◽  
Kylene Kehn-Hall ◽  
Megha Aggarwal ◽  
Nicole R. Bracci ◽  
Han-Chi Pan ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Fluorescent Protein ◽  
Glycogen Synthase ◽  
Venezuelan Equine Encephalitis Virus ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Luciferase Reporter ◽  
Venezuelan Equine Encephalitis ◽  
Equine Encephalitis Virus

The host proteins Protein Kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) are associated with multiple neurodegenerative disorders. They are also important for the replication of Venezuelan equine encephalitis virus (VEEV), thereby making the AKT/GSK-3 pathway an attractive target for developing anti-VEEV therapeutics. Resveratrol, a natural phytochemical, has been shown to substantially inhibit the AKT pathway. Therefore, we attempted to explore whether it exerts any antiviral activity against VEEV. In this study, we utilized green fluorescent protein (GFP)- and luciferase-encoding recombinant VEEV to determine the cytotoxicity and antiviral efficacy via luciferase reporter assays, flow cytometry, and immunofluorescent assays. Our results indicate that resveratrol treatment is capable of inhibiting VEEV replication, resulting in increased viability of Vero and U87MG cells as well as reduced virion production and viral RNA contents within host cells for at least 48 h with a single treatment. Furthermore, the suppression of apoptotic signaling adaptors, caspase-3, caspase-7, and annexin V may also be implicated in resveratrol-mediated antiviral activity. We found that decreased phosphorylation of the AKT/GSK-3 pathway, mediated by resveratrol, can be triggered during the early stages of VEEV infection, suggesting that resveratrol disrupts the viral replication cycle and consequently promotes cell survival. Finally, molecular docking and dynamics simulation studies revealed that resveratrol can directly bind to VEEV glycoproteins, which may interfere with virus attachment and entry. In conclusion, our results suggest that resveratrol exerts inhibitory activity against VEEV infection and upon further modification could be a useful compound to study in neuroprotective research and veterinary sciences.

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