Isolation of Anti-SARS-CoV-2 Natural Products Extracted from Mentha canadensis and the Semi-synthesis of Antiviral Derivatives.

Traditional herbal medicine offers opportunities to discover novel therapeutics against SARS-CoV-2 mutation. The dried aerial part of mint (Mentha canadensis L.) was chosen for bioactivity-guided extraction. Seven constituents were isolated and characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Syringic acid and methyl rosmarinate were evaluated in drug combination treatment. Ten amide derivatives of methyl rosmarinate were synthesized, and the dodecyl (13) and 3-ethylphenyl (19) derivatives demonstrated significant improvement in the anti-SARS-CoV-2 plaque reduction assay, achieving IC50 of 0.77 and 2.70 µM, respectively, against Omicron BA.1 as compared to methyl rosmarinate's IC50 of 57.0 µM. Spike protein binding and 3CLpro inhibition assays were performed to explore the viral inhibition mechanism. Molecular docking of compounds 13 and 19 to 3CLpro was performed to reveal potential interaction. In summary, natural products with anti-Omicron BA.1 activity were isolated from Mentha canadensis and derivatives of methyl rosmarinate were synthesized, showing 21- to 74-fold improvement in antiviral activity against Omicron BA.1.

Structural interactions of phytoconstituent(s) from cinnamon, bay leaf, oregano, and parsley with SARS-CoV-2 nucleocapsid protein: A comparative assessment for development of potential antiviral nutraceuticals.

SARS-CoV-2 has been responsible for causing 6,218,308 deaths globally till date and has garnered worldwide attention. The lack of effective preventive and therapeutic drugs against SARS-CoV-2 has further worsened the scenario and has bolstered research in the area. The N-terminal and C-terminal RNA binding domains (NTD and CTD) of SARS-CoV-2 nucleocapsid protein represent attractive therapeutic drug targets. Naturally occurring compounds are an excellent source of novel drug candidates due to their structural diversity and safety. Ten major bioactive compounds were identified in ethanolic extract (s) of Cinnamomum zeylanicum, Cinnamomum tamala, Origanum vulgare, and Petroselinum crispum using HPLC and their cytotoxic potential was determined against cancer and normal cell lines by MTT assay to ascertain their biological activity in vitro. To evaluate their antiviral potential, the binding efficacy to NTD and CTD of SARS-CoV-2 nucleocapsid protein was determined using in silico biology tools. In silico assessment of the phytocomponents revealed that most of the phytoconstituents displayed a druglike character with no predicted toxicity. Binding affinities were in the order apigenin > catechin > apiin toward SARS-CoV-2 nucleocapsid NTD. Toward nucleocapsid CTD, the affinity decreased as apigenin > cinnamic acid > catechin. Remdesivir displayed lesser affinity with NTD and CTD of SARS-CoV-2 nucleocapsid proteins than any of the studied phytoconstituents. Molecular dynamics (MD) simulation results revealed that throughout the 100 ns simulation, SARS-CoV-2 nucleocapsid protein NTD-apigenin complex displayed greater stability than SARS-CoV-2 nucleocapsid protein NTD-cinnamic acid complex. Hence, apigenin, catechin, apiin and cinnamic acid might prove as effective prophylactic and therapeutic candidates against SARS-CoV-2, if examined further in vitro and in vivo. PRACTICAL APPLICATIONS: Ten major bioactive compounds were identified in the extract(s) of four medicinally important plants viz. Cinnamomum zeylanicum, Cinnamomum tamala, Origanum vulgare and Petroselinum crispum using HPLC and their biological activity was also evaluated against cancer and normal cell lines. Interestingly, while all extract(s) wielded significant cytotoxicity against cancer cells, no significant toxicity was found against normal cells. The outcome of the results prompted evaluation of the antiviral potential of the ten bioactive compounds using in silico biology tools. The present study emphasizes on the application of computational approaches to understand the binding interaction and efficacy of the ten bioactive compounds from the above plants with SARS-CoV-2 nucleocapsid protein N-terminal and C-terminal RNA binding domains in preventing and/or treating COVID-19 using in silico tools. Druglikeness and toxicity profiles of the compounds were carried out to check the therapeutic application of the components. Additionally, molecular dynamics (MD) simulation was performed to check the stability of ligand-protein complexes. The results provided useful insights into the structural binding interaction(s) that can be exploited for the further development of potential antiviral agents targeting SARS-CoV-2 especially since no specific therapy is still available to combat the rapidly evolving virus and the existing treatment is more or less symptomatic which makes search for novel antiviral agents all the more necessary and crucial.

Natural products can be used in therapeutic management of COVID-19: Probable mechanistic insights.

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.

A Review of the Health Protective Effects of Phenolic Acids against a Range of Severe Pathologic Conditions (Including Coronavirus-Based Infections).

Phenolic acids comprise a class of phytochemical compounds that can be extracted from various plant sources and are well known for their antioxidant and anti-inflammatory properties. A few of the most common naturally occurring phenolic acids (i.e., caffeic, carnosic, ferulic, gallic, p-coumaric, rosmarinic, vanillic) have been identified as ingredients of edible botanicals (thyme, oregano, rosemary, sage, mint, etc.). Over the last decade, clinical research has focused on a number of in vitro (in human cells) and in vivo (animal) studies aimed at exploring the health protective effects of phenolic acids against the most severe human diseases. In this review paper, the authors first report on the main structural features of phenolic acids, their most important natural sources and their extraction techniques. Subsequently, the main target of this analysis is to provide an overview of the most recent clinical studies on phenolic acids that investigate their health effects against a range of severe pathologic conditions (e.g., cancer, cardiovascular diseases, hepatotoxicity, neurotoxicity, and viral infections-including coronaviruses-based ones).

Development and validation of a rapid high-performance thin-layer chromatographic method for quantification of gallic acid, cinnamic acid, piperine, eugenol, and glycyrrhizin in Divya-Swasari-Vati, an ayurvedic medicine for respiratory ailments.

Divya-Swasari-Vati is a calcium containing polyherbal ayurvedic medicine prescribed for the lung-related ailments observed in the current pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 infections. The formulation is a unique quintessential blend of nine herbs cited in Ayurvedic texts for chronic cough and lung infection. Analytical standardization of herbal medicines is the pressing need of the hour to ascertain the quality compliance. This persuaded us to develop a simple, rapid, and selective high-performance thin-layer chromatographic method for Divya-Swasari-Vati quality standardization. The developed method was validated for the quantification of marker components, gallic acid, cinnamic acid, piperine, eugenol and glycyrrhizin, against reference standards in five different batches of Divya-Swasari-Vati. The analytes were identified by visualization at 254 nm, and by matching their retention factor with authentic standards. The developed method was validated as per the guidelines recommended by the International Council for Harmonization for parameters like, linearity, limit of detection, limit of quantification, accuracy, and precision. Therefore, the developed novel high-performance thin-layer chromatographic process could be employed for rapid standardization of Divya-Swasari-Vati and other related herbal formulation, which would aid in quality manufacturing and product development.

Allergen fragrance molecules: a potential relief for COVID-19.

BACKGROUND: The latest coronavirus SARS-CoV-2, discovered in China and rapidly spread Worldwide. COVID-19 affected millions of people and killed hundreds of thousands worldwide. There are many ongoing studies investigating drug(s) suitable for preventing and/or treating this pandemic; however, there are no specific drugs or vaccines available to treat or prevent SARS-CoV-2 as of today. METHODS: Fifty-eight fragrance materials, which are classified as allergen fragrance molecules, were selected and used in this study. Docking simulations were carried out using four functional proteins; the Covid19 Main Protase (MPro), Receptor binding domain (RBD) of spike protein, Nucleocapsid, and host Bromodomain protein (BRD2), as target macromolecules. Three different software, AutoDock, AutoDock Vina (Vina), and Molegro Virtual Docker (MVD), running a total of four different docking protocol with optimized energy functions were used. Results were compared with the five molecules reported in the literature as potential drugs against COVID-19. Virtual screening was carried out using Vina, molecules satisfying our cut-off (- 6.5 kcal/mol) binding affinity was confirmed by MVD. Selected molecules were analyzed using the flexible docking protocol of Vina and AutoDock default settings. RESULTS: Ten out of 58 allergen fragrance molecules were selected for further docking studies. MPro and BRD2 are potential targets for the tested allergen fragrance molecules, while RBD and Nucleocapsid showed weak binding energies. According to AutoDock results, three molecules, Benzyl Cinnamate, Dihydroambrettolide, and Galaxolide, had good binding affinities to BRD2. While Dihydroambrettolide and Galaxolide showed the potential to bind to MPro, Sclareol and Vertofix had the best calculated binding affinities to this target. When the flexible docking results analyzed, all the molecules tested had better calculated binding affinities as expected. Benzyl Benzoate and Benzyl Salicylate showed good binding affinities to BRD2. In the case of MPro, Sclareol had the lowest binding affinity among all the tested allergen fragrance molecules. CONCLUSION: Allergen fragrance molecules are readily available, cost-efficient, and shown to be safe for human use. Results showed that several of these molecules had comparable binding affinities as the potential drug molecules reported in the literature to target proteins. Thus, these allergen molecules at correct doses could have significant health benefits.

Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target.

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.