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1.
Sci Rep ; 12(1): 5914, 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1784027

ABSTRACT

Secondary plant metabolites remain one of the key sources of therapeutic agents despite the development of new approaches for the discovery of medicinal drugs. In the current study, chemical analysis, and biological activities of Kei apple (Dovyalis caffra) methanolic extract were evaluated. Chemical analysis was performed using HPLC and GC-MS. Antiviral and anticancer effect were assessed using the crystal violet technique and activity against human liver cells (HepG2), respectively. Antibacterial activity was tested with the disc diffusion method. The obtained results showed that chlorogenic acid (2107.96 ± 0.07 µg/g), catechin (168 ± 0.58 µg/g), and gallic acid (15.66 ± 0.02 µg/g) were the main bioactive compounds identified by HPLC techniques. While, compounds containing furan moieties, as well as levoglucosenone, isochiapin B, dotriacontane, 7-nonynoic acid and tert-hexadecanethiol, with different biological activities were identified by GC-MS. Additionally, inhibition of 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) scavenging was 79.25% at 2000 µg/mL, indicating its antioxidant activity with IC50 of 728.20 ± 1.04 µg/mL. The tested extract exhibited potential anticancer activity (58.90% toxicity) against HepG2 cells at 1000 µg/mL. Potential bacterial inhibition was observed mainly against Escherichia coli and Proteus vulgaris, followed by Staphylococcus aureus and Bacillus subtilis with a diameter of growth inhibition ranging from 13 to 24 mm. While weak activities were recorded for fungi Candida albicans (10 mm). The extract showed mild antiviral activity against human coronavirus 229E with a selective index (SI) of 10.4, but not against human H3N2 (SI of 0.67). The molecular docking study's energy ratings were in good promise with the experiment documents of antibacterial and antiviral activities. The findings suggest that D. caffra juice extract is a potential candidate for further experiments to assess its use as potential alternative therapeutic agent.


Subject(s)
Antioxidants , Salicaceae , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/pharmacology , Antioxidants/chemistry , Antiviral Agents/analysis , Antiviral Agents/pharmacology , Fruit/chemistry , Humans , Influenza A Virus, H3N2 Subtype , Molecular Docking Simulation , Plant Extracts/chemistry
2.
Sci Rep ; 11(1): 22796, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1758351

ABSTRACT

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets.


Subject(s)
Antiviral Agents/analysis , Drug Evaluation, Preclinical/methods , SARS-CoV-2/drug effects , Biological Products/analysis , Biological Products/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Computational Biology/methods , Coronavirus 3C Proteases/drug effects , Coronavirus 3C Proteases/metabolism , Drug Discovery/methods , Flavonols/metabolism , Flavonols/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
3.
Mikrochim Acta ; 189(3): 125, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1712245

ABSTRACT

A novel electrochemical sensor is reported for the detection of the antiviral drug favipiravir based on the core-shell nanocomposite of flower-like molybdenum disulfide (MoS2) nanospheres and molecularly imprinted polymers (MIPs). The MoS2@MIP core-shell nanocomposite was prepared via the electrodeposition of a MIP layer on the MoS2 modified electrode, using o-phenylenediamine as the monomer and favipiravir as the template. The selective binding of target favipiravir at the MoS2@MIP core-shell nanocomposite produced a redox signal in a concentration dependent manner, which was used for the quantitative analysis. The preparation process of the MoS2@MIP core-shell nanocomposite was optimized. Under the optimal conditions, the sensor exhibited a wide linear response range of 0.01 ~ 100 nM (1.57*10-6 ~ 1.57*10-2 µg mL-1) and a low detection limit of 0.002 nM (3.14*10-7 µg mL-1). Application of the sensor was demonstrated by detecting favipiravir in a minimum amount of 10 µL biological samples (urine and plasma). Satisfied results in the recovery tests indicated a high potential of favipiravir monitoring in infectious COVID-19 samples.


Subject(s)
Amides/analysis , Antiviral Agents/analysis , Disulfides/chemistry , Molecularly Imprinted Polymers/chemistry , Molybdenum/chemistry , Nanocomposites/chemistry , Nanospheres/chemistry , Pyrazines/analysis , Amides/blood , Amides/therapeutic use , Amides/urine , Antiviral Agents/blood , Antiviral Agents/therapeutic use , Antiviral Agents/urine , COVID-19/drug therapy , COVID-19/virology , Electrochemical Techniques/methods , Humans , Limit of Detection , Oxidation-Reduction , Pyrazines/blood , Pyrazines/therapeutic use , Pyrazines/urine , Reproducibility of Results , SARS-CoV-2/isolation & purification
4.
Microbiol Spectr ; 9(3): e0109121, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1591660

ABSTRACT

Chemical methods of virus inactivation are used routinely to prevent viral transmission in both a personal hygiene capacity but also in at-risk environments like hospitals. Several virucidal products exist, including hand soaps, gels, and surface disinfectants. Resin acids, which can be derived from tall oil, produced from trees, have been shown to exhibit antibacterial activity. However, whether these products or their derivatives have virucidal activity is unknown. Here, we assessed the capacity of rosin soap to inactivate a panel of pathogenic mammalian viruses in vitro. We show that rosin soap can inactivate human enveloped viruses: influenza A virus (IAV), respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For IAV, rosin soap could provide a 100,000-fold reduction in infectivity. However, rosin soap failed to affect the nonenveloped encephalomyocarditis virus (EMCV). The inhibitory effect of rosin soap against IAV infectivity was dependent on its concentration but not on the incubation time or temperature. In all, we demonstrate a novel chemical inactivation method against enveloped viruses, which could be of use for preventing virus infections in certain settings. IMPORTANCE Viruses remain a significant cause of human disease and death, most notably illustrated through the current coronavirus disease 2019 (COVID-19) pandemic. Control of virus infection continues to pose a significant global health challenge to the human population. Viruses can spread through multiple routes, including via environmental and surface contamination, where viruses can remain infectious for days. Methods for inactivating viruses on such surfaces may help mitigate infection. Here, we present evidence identifying a novel virucidal product, rosin soap, which is produced from tall oil from coniferous trees. Rosin soap was able to rapidly and potently inactivate influenza virus and other enveloped viruses.


Subject(s)
Antiviral Agents/pharmacology , Resins, Plant/pharmacology , Soaps/pharmacology , Antiviral Agents/analysis , Influenza A virus/drug effects , Influenza A virus/growth & development , Plant Oils/analysis , Plant Oils/pharmacology , Resins, Plant/analysis , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , Soaps/analysis , Virus Inactivation/drug effects
5.
Biomed Pharmacother ; 146: 112513, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1575252

ABSTRACT

The interactions of four sulfonylated Phe(3-Am)-derived inhibitors (MI-432, MI-463, MI-482 and MI-1900) of type II transmembrane serine proteases (TTSP) such as transmembrane protease serine 2 (TMPRSS2) were examined with serum albumin and cytochrome P450 (CYP) isoenzymes. Complex formation with albumin was investigated using fluorescence spectroscopy. Furthermore, microsomal hepatic CYP1A2, 2C9, 2C19 and 3A4 activities in presence of these inhibitors were determined using fluorometric assays. The inhibitory effects of these compounds on human recombinant CYP3A4 enzyme were also examined. In addition, microsomal stability assays (60-min long) were performed using an UPLC-MS/MS method to determine depletion percentage values of each compound. The inhibitors showed no or only weak interactions with albumin, and did not inhibit CYP1A2, 2C9 and 2C19. However, the compounds tested proved to be potent inhibitors of CYP3A4 in both assays performed. Within one hour, 20%, 12%, 14% and 25% of inhibitors MI-432, MI-463, MI-482 and MI-1900, respectively, were degraded. As essential host cell factor for the replication of the pandemic SARS-CoV-2, the TTSP TMPRSS2 emerged as an important target in drug design. Our study provides further preclinical data on the characterization of this type of inhibitors for numerous trypsin-like serine proteases.


Subject(s)
Antiviral Agents/metabolism , Cytochrome P-450 Enzyme System/metabolism , Protease Inhibitors/metabolism , Serine Endopeptidases/metabolism , Serum Albumin, Human/metabolism , Antiviral Agents/analysis , Antiviral Agents/pharmacology , Dose-Response Relationship, Drug , Humans , Isoenzymes/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protease Inhibitors/analysis , Protease Inhibitors/pharmacology , Protein Binding/physiology , Serine Endopeptidases/analysis , Spectrometry, Fluorescence/methods , Tandem Mass Spectrometry/methods
6.
Assay Drug Dev Technol ; 19(8): 475-483, 2021.
Article in English | MEDLINE | ID: covidwho-1475724

ABSTRACT

Corona virus disease 2019 (COVID-19) has posed a mounting threat to public health with worldwide outbreak caused by a novel virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recently, remdesivir (RDV) has been approved by Food and Drug Administration (FDA) for treating COVID-19 patients ≥12 years old requiring hospitalization. To the best of our knowledge, a simple method to estimate RDV in the pharmaceutical formulations using high-performance liquid chromatography (HPLC) is still unexplored, highlighting the need for a precise analytical method for its quantification. The prime purpose of the current investigation was to develop and validate a well-grounded HPLC method for quantification of RDV in pharmaceutical formulations. The best chromatogram was obtained by means of an Inertsil ODS-3V column using a mobile phase of milli-Q water modified to pH 3.0 with o-phosphoric acid and acetonitrile (50:50, % v/v) at a flow rate of 1.2 mL/min and wavelength of detector set at 246 nm with retention time being achieved at 6.0 min. The method was validated following International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 (R1) guidelines for various parameters such as specificity and selectivity, system suitability, linearity, precision, accuracy, limits of detection and quantification, and robustness. The method developed for the quantification of RDV was found to be linear in the concentration range of 25-2,500 ng/mL with limit of detection and limit of quantification of 1.95 and 6.49 ng/mL, respectively. Assay value of 102% ± 1% was achieved for marketed injectable dosage form when estimated by the validated method. Therefore, in this study a simple, rapid, sensitive, selective, accurate, precise, and robust analytical method was developed and validated for the quantification of RDV using HPLC. The established method was successfully employed for quantification of RDV in marketed pharmaceutical formulation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Administration, Intravenous/standards , Alanine/analogs & derivatives , Antiviral Agents/administration & dosage , Antiviral Agents/analysis , COVID-19/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analysis , Adenosine Monophosphate/chemistry , Administration, Intravenous/methods , Alanine/administration & dosage , Alanine/analysis , Alanine/chemistry , Antiviral Agents/chemistry , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Dosage Forms/standards , Humans , Reproducibility of Results
7.
Bioorg Chem ; 116: 105362, 2021 11.
Article in English | MEDLINE | ID: covidwho-1432980

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a serious threat to global health. One attractive antiviral target is the membrane fusion mechanism employed by the virus to gain access to the host cell. Here we report a robust protein-based fluorescent polarization assay, that mimicking the formation of the six-helix bundle (6-HB) process during the membrane fusion, for the evaluation and screening of SARS-CoV-2 fusion Inhibitors. The IC50 of known inhibitors, HR2P, EK1, and Salvianolic acid C (Sal-C) were measured to be 6.1 nM, 2.5 nM, and 8.9 µM respectively. In addition, we found Sal-A has a slightly lower IC50 (3.9 µM) than Sal-C. Interestingly, simple caffeic acid can also disrupt the formation of 6-HB with a sub-mM concentration. Pilot high throughput screening (HTS) of a small marine natural product library validates the assay with a Z' factor close to 0.8. We envision the current assay provides a convenient way to screen SARS-CoV-2 fusion inhibitors and assess their binding affinity.


Subject(s)
Alkenes/analysis , Antiviral Agents/analysis , Fluorescence Polarization , High-Throughput Screening Assays , Peptides/analysis , Polyphenols/analysis , Alkenes/pharmacology , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Structure , Peptides/pharmacology , Polyphenols/pharmacology , SARS-CoV-2/drug effects
8.
Int J Mol Sci ; 22(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1372662

ABSTRACT

Natural products of microbial origin have inspired most of the commercial pharmaceuticals, especially those from Actinobacteria. However, the redundancy of molecules in the discovery process represents a serious issue. The untargeted approach, One Strain Many Compounds (OSMAC), is one of the most promising strategies to induce the expression of silent genes, especially when combined with genome mining and advanced metabolomics analysis. In this work, the whole genome of the marine isolate Rhodococcus sp. I2R was sequenced and analyzed by antiSMASH for the identification of biosynthetic gene clusters. The strain was cultivated in 22 different growth media and the generated extracts were subjected to metabolomic analysis and functional screening. Notably, only a single growth condition induced the production of unique compounds, which were partially purified and structurally characterized by liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS). This strategy led to identifying a bioactive fraction containing >30 new glycolipids holding unusual functional groups. The active fraction showed a potent antiviral effect against enveloped viruses, such as herpes simplex virus and human coronaviruses, and high antiproliferative activity in PC3 prostate cancer cell line. The identified compounds belong to the biosurfactants class, amphiphilic molecules, which play a crucial role in the biotech and biomedical industry.


Subject(s)
Antiviral Agents/metabolism , Glycolipids/metabolism , Rhodococcus/metabolism , Animals , Antiviral Agents/analysis , Chlorocebus aethiops , Culture Techniques , Drug Screening Assays, Antitumor , Esters/metabolism , Genome, Bacterial , Glycolipids/chemistry , Humans , Metabolome , Microbial Sensitivity Tests , Molecular Structure , PC-3 Cells , Rhodococcus/chemistry , Rhodococcus/genetics , Succinates/metabolism , Surface-Active Agents/chemistry , Surface-Active Agents/metabolism , Vero Cells
9.
Molecules ; 26(13)2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1288957

ABSTRACT

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.


Subject(s)
Amides/analysis , Amides/blood , Antiviral Agents/analysis , Antiviral Agents/blood , Biological Assay/methods , COVID-19/drug therapy , Chromatography, High Pressure Liquid/methods , Liquid-Liquid Extraction/methods , Pyrazines/analysis , Pyrazines/blood , Acyclovir/analysis , Acyclovir/blood , COVID-19/blood , Calibration , Drug Stability , Freezing , Humans , Reference Standards , Reproducibility of Results , Solvents/chemistry
11.
Inorg Chem ; 60(9): 6585-6599, 2021 May 03.
Article in English | MEDLINE | ID: covidwho-1195597

ABSTRACT

Silver vanadate nanorods (ß-AgVO3) with silver nanoparticles (Ag-NPs) decorated on the surface of the rods were synthesized by using simple hydrothermal technique and later anchored onto nitrogen-doped reduced graphene oxide (N-rGO) to make a novel nanocomposite. Experimental analyses were carried out to identify the electronic configuration by X-ray diffraction analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy analysis, which revealed monoclinic patterns of the C12/m1 space group with Wulff construction forming beta silver vanadate (ß-AgVO3) crystals with optical density and phase transformations. Ag nucleation showed consistent results with metallic formation and electronic changes occurring in [AgO5] and [AgO3] clusters. Transmission electron microscopy and field-emission scanning electron microscopy with elemental mapping and EDX analysis of the morphology reveals the nanorod structure for ß-AgVO3 with AgNPs on the surface and sheets for N-rGO. Additionally, a novel electrochemical sensor is constructed by using Ag/AgVO3/N-rGO on screen-printed carbon paste electrodes for the detection of antiviral drug levofloxacin (LEV) which is used as a primary antibiotic in controlling COVID-19. Using differential pulse voltammetry, LEV is determined with a low detection limit of 0.00792 nm for a linear range of 0.09-671 µM with an ultrahigh sensitivity of 152.19 µA µM-1 cm-2. Furthermore, modified electrode performance is tested by real-time monitoring using biological and river samples.


Subject(s)
Dielectric Spectroscopy/instrumentation , Dielectric Spectroscopy/methods , Levofloxacin/analysis , Nanocomposites/chemistry , Antiviral Agents/analysis , Antiviral Agents/blood , Antiviral Agents/urine , Carbon/chemistry , Electrodes , Graphite/chemistry , Humans , Levofloxacin/blood , Levofloxacin/urine , Limit of Detection , Metal Nanoparticles/chemistry , Microscopy, Electron, Transmission , Nanotubes/chemistry , Photoelectron Spectroscopy , Silver/chemistry , Silver Compounds/chemistry , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Tablets , Vanadates/chemistry , X-Ray Diffraction
12.
Chem Biodivers ; 17(11): e2000707, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1193067

ABSTRACT

Lodoicea maldivica (J.F.Gmel.) Pers. (Arecaceae), 'Coco de Mer', is a palm, growing as endemic in the Seychelles islands. Its fruit weighs up to 20 kg and is characterized by a fleshy and fibrous envelope surrounding the nutlike portion. The present work combines a morpho-anatomical and a phytochemical analysis of the fruit exocarp and mesocarp. The exocarp is composed by a layer of palisade cells. The mesocarp is characterized by vascular bundles and by sclereids. In the aerenchyma, the internal zone of the mesocarp, cells aggregates were positive to phenols, while idioblasts were positive to terpenes. We performed a GC/MS analysis with a semi-quantitative relative amount calculation of the recorded compounds. The GC/MS essential oil profile revealed the dominance of acyclic sesquiterpenoids (53.95 %), followed by bicyclic sesquiterpenoids (31.69 %), monoterpenes (11.89 %) and monocyclic sesquiterpenoids (2.44 %). The terpenes detected in higher amounts, ß-caryophyllene and bicyclogermacrene, are known for activity against insect larvae, but have been proposed as antiviral candidates against SARS-CoV-2. The third compound in amount, aromadendrene, is active against bacteria and, again, known to possess insecticidal properties.


Subject(s)
Cocos/chemistry , Fruit/chemistry , Oils, Volatile/analysis , Anti-Bacterial Agents/analysis , Antiviral Agents/analysis , Azulenes/analysis , Betacoronavirus/drug effects , COVID-19 , Cocos/ultrastructure , Coronavirus Infections/drug therapy , Fruit/ultrastructure , Gas Chromatography-Mass Spectrometry , Humans , Insecticides/analysis , Monoterpenes/analysis , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Sesquiterpenes/analysis
13.
Magn Reson Chem ; 59(7): 746-751, 2021 07.
Article in English | MEDLINE | ID: covidwho-1182204

ABSTRACT

Favipiravir is an established antiviral that is currently being assessed as an investigational drug for the treatment of COVID-19. Favipiravir is strikingly similar to two molecules that the World Health Organization (WHO) lists as essential medicines, which also consist of a six-membered aromatic N-heterocycle bearing a carboxamide function: the anti-tuberculosis agent, pyrazinamide, and nicotinamide, also known as vitamin B3 . We demonstrate the utility of 1 H nuclear magnetic resonance (NMR) profiling, an emerging pharmacopoeial tool, for the highly specific identification, selective differentiation of congeners, and subsequent detection of drug falsification or adulteration of these medicines. The straightforward comparison of basic 1-D 1 H NMR spectra, obtained with benchtop or advanced NMR instruments alike, offers a rapid identity assay and works independently of physical reference materials. This approach accelerates and advances pharmaceutical quality control measures under situations of increased drug demand and altered economy, such as during a pandemic.


Subject(s)
Amides/analysis , Antiviral Agents/analysis , Drug Contamination/prevention & control , Niacinamide/analysis , Pyrazinamide/analysis , Pyrazines/analysis , Quality Control , Amides/chemistry , Antiviral Agents/chemistry , Niacinamide/chemistry , Proton Magnetic Resonance Spectroscopy , Pyrazinamide/chemistry , Pyrazines/chemistry , World Health Organization
14.
Front Public Health ; 8: 589736, 2020.
Article in English | MEDLINE | ID: covidwho-1143436

ABSTRACT

COVID-19 pandemic since the end of 2019 spreads worldwide, counting millions of victims. The viral invasion, systemic inflammation, and consequent organ failure are the gravest features of coronavirus disease 2019 (COVID-19), and they are associated with a high mortality rate. The aim of this study is to evaluate the role of breast milk in the COVID-19 pandemic, analyzing its antiviral, anti-inflammatory, and immunoregulatory effects due to its bioactive components, so numerous and important for the protection of infants. The study tried to demonstrate that all the components of human milk are capable of performing functions on all the pathogenic events recognized and described in COVID-19 disease. Those human milk factors are well-tolerated and practically free of side effects, so breast milk should become a research topic to discover therapies even in this epidemic. In the first part, the mechanisms of protection and defense of the breast milk elements will be delineated; in the second section, it will describe the human milk effects in viral infections and it will be hypothesized how the known mechanisms could act in COVID infection.


Subject(s)
Anti-Infective Agents/analysis , Anti-Inflammatory Agents/analysis , Antiviral Agents/analysis , COVID-19/prevention & control , Immunologic Factors/analysis , Milk, Human/chemistry , Milk, Human/virology , Adult , Female , Humans , Infant , Infant, Newborn , Male , Pandemics/prevention & control , SARS-CoV-2
15.
Molecules ; 26(6)2021 Mar 21.
Article in English | MEDLINE | ID: covidwho-1143541

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there is no effective specific treatment for the disease. Aloe is a rich source of isolated phytoconstituents that have an enormous range of biological activities. Since there are no available experimental techniques to examine these compounds for antiviral activity against SARS-CoV-2, we employed an in silico approach involving molecular docking, dynamics simulation, and binding free energy calculation using SARS-CoV-2 essential proteins as main protease and spike protein to identify lead compounds from Aloe that may help in novel drug discovery. Results retrieved from docking and molecular dynamics simulation suggested a number of promising inhibitors from Aloe. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) calculations indicated that compounds 132, 134, and 159 were the best scoring compounds against main protease, while compounds 115, 120, and 131 were the best scoring ones against spike glycoprotein. Compounds 120 and 131 were able to achieve significant stability and binding free energies during molecular dynamics simulation. In addition, the highest scoring compounds were investigated for their pharmacokinetic properties and drug-likeness. The Aloe compounds are promising active phytoconstituents for drug development for SARS-CoV-2.


Subject(s)
Aloe/chemistry , Antiviral Agents/analysis , Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Development , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Computational Biology , Coronavirus 3C Proteases/metabolism , Drug Discovery/methods , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals/analysis , Phytochemicals/chemistry , Phytochemicals/metabolism , Phytochemicals/pharmacokinetics , Protein Binding , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119388, 2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1142229

ABSTRACT

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded NH⋯O intermolecular interactions and two weak hydrogen bonded CH⋯O interactions. The red shift in NH stretching frequency exposed from IR substantiates the formation of NH⋯O intermolecular hydrogen bond and the blue shift in CH stretching frequency substantiates the formation of CH⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Chromones , Coronavirus 3C Proteases/antagonists & inhibitors , Drugs, Investigational , SARS-CoV-2/drug effects , Thiourea , Antiviral Agents/analysis , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Chromones/analysis , Chromones/chemical synthesis , Chromones/chemistry , Chromones/pharmacokinetics , Computational Chemistry , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Drugs, Investigational/analysis , Drugs, Investigational/chemical synthesis , Drugs, Investigational/chemistry , Drugs, Investigational/pharmacokinetics , Humans , Hydrazines/chemistry , Hydrogen/chemistry , Hydrogen Bonding , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Protein Binding , Quantum Theory , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Thioamides/analysis , Thioamides/chemical synthesis , Thioamides/chemistry , Thioamides/pharmacokinetics , Thiourea/analysis , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacokinetics , Vibration
17.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119241, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1065570

ABSTRACT

The present work describes development of rapid, robust, sensitive and green spectrofluorimetric method for determination of favipiravir (FAV). Different factors affecting fluorescence were carefully studied and Box Behnken Design was applied to optimize experimental parameters. The proposed method is based on measuring native fluorescence of FAV in 0.2 M borate buffer (pH 8.0) at 432 nm after excitation at 361 nm. There was a linear relationship between FAV concentration and relative fluorescence intensity over the range 40-280 ng/mL with limit of detection of 9.44 ng/mL and quantitation limit of 28.60 ng/mL. The method was successfully implemented for determination of FAV in its pharmaceutical formulation with mean % recovery of 99.26 ± 0.87. Moreover, the high sensitivity of the method allowed determination of FAV in spiked human plasma over a range of 48-192 ng/mL. The proposed spectrofluorimetric method was proved to be eco-friendly according to analytical eco-scale.


Subject(s)
Amides/blood , Antiviral Agents/blood , COVID-19/blood , COVID-19/drug therapy , Pyrazines/blood , Spectrometry, Fluorescence/methods , Amides/analysis , Amides/therapeutic use , Antiviral Agents/analysis , Antiviral Agents/therapeutic use , Blood Chemical Analysis/methods , Blood Chemical Analysis/statistics & numerical data , Humans , Limit of Detection , Pyrazines/analysis , Pyrazines/therapeutic use , SARS-CoV-2 , Sensitivity and Specificity , Spectrometry, Fluorescence/statistics & numerical data
18.
J Pharm Biomed Anal ; 194: 113806, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1065380

ABSTRACT

Remdesivir is a prodrug of the nucleotide analogue and used for COVID-19 treatment. However, the bioanalysis of the active metabolites remdesivir nucleotide triphosphate (RTP) and its precursor remdesivir nucleotide monophosphate (RMP) is very challenging. Herein, we established a novel method to separate RTP and RMP on a BioBasic AX column and quantified them by high-performance liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. Stepwise, we optimized chromatographic retention on an anion exchange column, improved stability in matrix through the addition of 5,5'-dithiobis-(2nitrobenzoic acid) and PhosSTOP EASYpack, and increased recovery by dissociation of tight protein binding with 2 % formic acid aqueous solution. The method allowed lower limit of quantification of 20 nM for RMP and 10 nM for RTP. Method validation demonstrated acceptable accuracy (93.6%-103% for RMP, 94.5%-107% for RTP) and precision (RSD < 11.9 % for RMP, RSD < 11.4 % for RTP), suggesting that it was sensitive and robust for simultaneous quantification of RMP and RTP. The method was successfully applied to analyze RMP and RTP in mouse tissues. In general, the developed method is suitable to monitor RMP and RTP, and provides a useful approach for exploring more detailed effects of remdesivir in treating diseases.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Prodrugs/analysis , Prodrugs/metabolism , Tandem Mass Spectrometry/methods , Adenosine Monophosphate/analysis , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analysis , Alanine/metabolism , Alanine/pharmacology , Animals , Antiviral Agents/analysis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Chromatography, Liquid/methods , Humans , Liver/chemistry , Liver/drug effects , Liver/metabolism , Male , Mice , Prodrugs/pharmacology
19.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119388, 2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1049871

ABSTRACT

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded NH⋯O intermolecular interactions and two weak hydrogen bonded CH⋯O interactions. The red shift in NH stretching frequency exposed from IR substantiates the formation of NH⋯O intermolecular hydrogen bond and the blue shift in CH stretching frequency substantiates the formation of CH⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Chromones , Coronavirus 3C Proteases/antagonists & inhibitors , Drugs, Investigational , SARS-CoV-2/drug effects , Thiourea , Antiviral Agents/analysis , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Chromones/analysis , Chromones/chemical synthesis , Chromones/chemistry , Chromones/pharmacokinetics , Computational Chemistry , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Drugs, Investigational/analysis , Drugs, Investigational/chemical synthesis , Drugs, Investigational/chemistry , Drugs, Investigational/pharmacokinetics , Humans , Hydrazines/chemistry , Hydrogen/chemistry , Hydrogen Bonding , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Protein Binding , Quantum Theory , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Thioamides/analysis , Thioamides/chemical synthesis , Thioamides/chemistry , Thioamides/pharmacokinetics , Thiourea/analysis , Thiourea/chemical synthesis , Thiourea/chemistry , Thiourea/pharmacokinetics , Vibration
20.
Drug Discov Ther ; 14(6): 273-281, 2021 Jan 23.
Article in English | MEDLINE | ID: covidwho-1006068

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is undoubtedly the most challenging pandemic in the current century. A total of 73,953,702 confirmed cases of COVID-19 and 1,644,416 deaths were reported globally up to December 17, 2020. Therefore, in the absence of a safe and effective vaccine, it is urgent to identify a novel antiviral drug to effectively treat patients with COVID-19. On October 22, the U.S. Food and Drug Administration approved remdesivir, a nucleotide analog prodrug with broad antiviral activity, for adults and children (12 years of age and older and weighing at least 40 kg) who need to be admitted to hospital for covid-19 treatment. In order to monitor the optimization of patient clinical response profile, as well as address the challenges associated with remdesivir metabolism, highly sensitive, selective and accurate analytical methods are necessary. This review clearly covers all the analytical methods developed for the identification and quantitative determination of remdesivir and its metabolites in biological matrices, which helps the researchers in developing new methods for the analysis of remdesivir by considering the pros and cons of the previously reported methods.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/analysis , COVID-19/drug therapy , Drug Monitoring/methods , Adenosine Monophosphate/analysis , Adenosine Monophosphate/pharmacokinetics , Alanine/analysis , Alanine/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/diagnosis , COVID-19/virology , Humans , Predictive Value of Tests , Treatment Outcome
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