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1.
Int J Mol Sci ; 23(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613825

ABSTRACT

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.


Subject(s)
Antiviral Agents/chemical synthesis , Cellulose/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Nucleosides/chemical synthesis , SARS-CoV-2/enzymology , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacokinetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacokinetics , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacokinetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Computational Biology , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Nucleosides/chemistry , Nucleosides/pharmacokinetics , Pyrolysis , SARS-CoV-2/drug effects
2.
SAR QSAR Environ Res ; 32(11): 863-888, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1606722

ABSTRACT

The novel severe acute respiratory syndrome coronavirus (SARS CoV-2) was introduced as an epidemic in 2019 and had millions of deaths worldwide. Given the importance of this disease, the recommendation and design of new active compounds are crucial. 3-chymotrypsin-like protease (3 CLpro) inhibitors have been identified as potent compounds for treating SARS-CoV-2 disease. So, the design of new 3 CLpro inhibitors was proposed using a quantitative structure-activity relationship (QSAR) study. In this context, a powerful adaptive least absolute shrinkage and selection operator (ALASSO) penalized variable selection method with inherent advantages coupled with a nonlinear artificial neural network (ANN) modelling method were used to provide a QSAR model with high interpretability and predictability. After evaluating the accuracy and validity of the developed ALASSO-ANN model, new compounds were proposed using effective descriptors, and the biological activity of the new compounds was predicted. Ligand-receptor (LR) interactions were also performed to confirm the interaction strength of the compounds using molecular docking (MD) study. The pharmacokinetics properties and calculated Lipinski's rule of five were applied to all proposed compounds. Due to the ease of synthesis of these suggested new compounds, it is expected that they have acceptable pharmacological properties.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/pharmacokinetics , Coronavirus 3C Proteases/chemistry , Inhibitory Concentration 50 , Molecular Docking Simulation , Neural Networks, Computer , Protease Inhibitors/pharmacokinetics , Quantitative Structure-Activity Relationship , Reproducibility of Results , SARS-CoV-2/enzymology
3.
Nat Commun ; 12(1): 6097, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475295

ABSTRACT

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Lung/metabolism , Lung/virology , Macaca fascicularis , Male , Mesocricetus , Mice , Mice, Transgenic , SARS-CoV-2/isolation & purification , Tissue Distribution , Viral Load
4.
Int J Biol Macromol ; 191: 1114-1125, 2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1442393

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Biological Products/pharmacokinetics , Biological Products/toxicity , Computer Simulation , Drug Evaluation, Preclinical/methods , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
5.
Placenta ; 115: 70-77, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433733

ABSTRACT

Species differences are among the main reasons for the high failure rate of preclinical studies. A better awareness and understanding of these differences might help to improve the outcome of preclinical research. In reproduction, the placenta is the central organ regulating fetal exposure to a substance circulating in the maternal organism. Exact information about placental transfer can help to better estimate the toxic potential of a substance. From an evolutionary point of view, the chorioallantoic placenta is the organ with the highest anatomical diversity among species. Moreover, frequently used animal models in reproduction belong to rodents and lagomorphs, two groups that are characterized by the generation of an additional type of placenta, which is crucial for fetal development, but absent from humans: the inverted yolk sac placenta. Taken together, the translatability of placental transfer studies from laboratory animals to humans is challenging, which is supported by the fact that numerous species-dependent toxic effects are described in literature. Thus, reliable human-relevant data are frequently lacking and the toxic potential of chemicals and pharmaceuticals for humans can hardly be estimated, often resulting in recommendations that medical treatments or exposure to chemicals should be avoided for safety reasons. Although species differences of placental anatomy have been described frequently and the need for human-relevant research models has been emphasized, analyses of substances with species-dependent placental transfer have been performed only sporadically. Here, we present examples for species-specific placental transfer, including that of nanoparticles and pharmaceuticals, and discuss potential underlying mechanisms. With respect to the COVID 19-pandemic it might be of interest that some antiviral drugs are reported to feature species-specific placental transfer. Further, differences in placental structure and antibody transfer may affect placental transfer of ZIKA virus.


Subject(s)
Maternal-Fetal Exchange/physiology , Placenta/metabolism , Animals , Antiviral Agents/pharmacokinetics , Biological Transport/physiology , COVID-19/drug therapy , COVID-19/transmission , COVID-19/virology , Female , Humans , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange/drug effects , Placenta/drug effects , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/metabolism , Pregnancy Complications, Infectious/virology , SARS-CoV-2/metabolism , Species Specificity , Yolk Sac/metabolism , Yolk Sac/physiology , Zika Virus/metabolism , Zika Virus Infection/drug therapy , Zika Virus Infection/transmission
6.
Bioorg Med Chem ; 46: 116364, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1406212

ABSTRACT

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Adenosine/pharmacokinetics , Adenosine/pharmacology , Adenosine/toxicity , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Chlorocebus aethiops , Male , Mice, Inbred ICR , Microbial Sensitivity Tests , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/toxicity , Vero Cells
7.
Eur J Pharmacol ; 890: 173648, 2021 Jan 05.
Article in English | MEDLINE | ID: covidwho-1385504

ABSTRACT

In an attempt to search for selective inhibitors against the SARS-CoV-2 which caused devastating of lives and livelihoods across the globe, 415 natural metabolites isolated from several plants, fungi and bacteria, belonging to different classes, were investigated. The drug metabolism and safety profiles were computed in silico and the results showed seven compounds namely fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxin B and D, and stagonolide K were predicted to having considerable absorption, metabolism, distribution and excretion parameters (ADME) and safety indices. Molecular docking against the receptor binding domain (RBD) of spike glycoprotein (S1) and the main protease (Mpro) exposed the compounds having better binding affinity to main protease as compared to the S1 receptor binding domain. The docking results were compared to an antiviral drug penciclovir reportedly of clinical significance in treating the SARS-CoV-2 infected patients. The results demonstrated the test compounds jasmonic acid, putaminoxins B and D bound to the HIS-CYS catalytic dyad as well as to other residues within the MPro active site with much greater affinity than penciclovir. The findings of the study suggest that these compounds could be explored as potential SARS-CoV-2 inhibitors, and could further be combined with the experimental investigations to develop effective therapeutics to deal with the present pandemic.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Coronavirus 3C Proteases/metabolism , Phytochemicals/pharmacology , Protease Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Antiviral Agents/pharmacokinetics , Bacteria/metabolism , Biological Products/pharmacokinetics , Blood-Brain Barrier/metabolism , Coronavirus 3C Proteases/antagonists & inhibitors , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , Fungi/metabolism , Humans , Intestinal Absorption , Lactones/pharmacokinetics , Lactones/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Oxylipins/pharmacokinetics , Oxylipins/pharmacology , Phytochemicals/pharmacokinetics , Plants/metabolism , Protease Inhibitors/pharmacokinetics , Protein Binding , Protein Domains , SARS-CoV-2
9.
Int J Nanomedicine ; 16: 4959-4984, 2021.
Article in English | MEDLINE | ID: covidwho-1334842

ABSTRACT

Antiviral drugs (AvDs) are the primary resource in the global battle against viruses, including the recent fight against corona virus disease 2019 (COVID-19). Most AvDs require multiple medications, and their use frequently leads to drug resistance, since they have poor oral bioavailability and low efficacy due to their low solubility/low permeability. Characterizing the in vivo metabolism and pharmacokinetic characteristics of AvDs may help to solve the problems associated with AvDs and enhance their efficacy. In this review of AvDs, we systematically investigated their structure-based metabolic reactions and related enzymes, their cellular pharmacology, and the effects of metabolism on AvD pharmacodynamics and pharmacokinetics. We further assessed how delivery systems achieve better metabolism and pharmacology of AvDs. This review suggests that suitable nanosystems may help to achieve better pharmacological activity and pharmacokinetic behavior of AvDs by altering drug metabolism through the utilization of advanced nanotechnology and appropriate administration routes. Notably, such AvDs as ribavirin, remdesivir, favipiravir, chloroquine, lopinavir and ritonavir have been confirmed to bind to the severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) receptor and thus may represent anti-COVID-19 treatments. Elucidating the metabolic and pharmacokinetic characteristics of AvDs may help pharmacologists to identify new formulations with high bioavailability and efficacy and help physicians to better treat virus-related diseases, including COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/metabolism , Drug Delivery Systems , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans
10.
Drugs R D ; 21(3): 273-283, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1330440

ABSTRACT

BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.


Subject(s)
Angiotensin-Converting Enzyme 2/drug effects , Antiviral Agents/pharmacology , Peptides/pharmacology , Spike Glycoprotein, Coronavirus/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Computer Simulation , Drug Design , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Peptides/pharmacokinetics , Peptides/toxicity , Protein Binding/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Substrate Specificity
11.
Bioorg Chem ; 115: 105196, 2021 10.
Article in English | MEDLINE | ID: covidwho-1322004

ABSTRACT

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1ß, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.


Subject(s)
Antiviral Agents/pharmacology , Piperidines/pharmacology , Quinolizidines/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Cathepsin B/antagonists & inhibitors , Chlorocebus aethiops , Cytokines/metabolism , HEK293 Cells , Humans , Male , Mice , Microbial Sensitivity Tests , Molecular Structure , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Piperidines/toxicity , Quinolizidines/chemical synthesis , Quinolizidines/pharmacokinetics , Quinolizidines/toxicity , Rats, Sprague-Dawley , Structure-Activity Relationship , Vero Cells
12.
Anal Bioanal Chem ; 413(23): 5811-5820, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1321733

ABSTRACT

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Adenosine/blood , Adenosine/pharmacokinetics , Adenosine/standards , Adenosine Monophosphate/blood , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/standards , Alanine/blood , Alanine/pharmacokinetics , Alanine/standards , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/standards , Limit of Detection , Male , Quality Control , Rats , Rats, Sprague-Dawley , Reference Standards , Reproducibility of Results
13.
CPT Pharmacometrics Syst Pharmacol ; 10(10): 1161-1170, 2021 10.
Article in English | MEDLINE | ID: covidwho-1320090

ABSTRACT

The antiretroviral drug favipiravir (FPV) inhibits RNA-dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID-19). However, its pharmacokinetics in patients with COVID-19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography-tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27-89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11-2.2 m2 ), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one-compartment model with first-order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID-19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID-19, but dose-dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.


Subject(s)
Amides/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/drug therapy , Pyrazines/administration & dosage , Adult , Aged , Aged, 80 and over , Amides/pharmacokinetics , Antiviral Agents/pharmacokinetics , COVID-19/blood , Chromatography, Liquid , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Models, Theoretical , Pyrazines/pharmacokinetics , Retrospective Studies , Tandem Mass Spectrometry , Treatment Outcome
14.
Molecules ; 26(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1304689

ABSTRACT

Antiviral action of various photosensitizers is already summarized in several comprehensive reviews, and various mechanisms have been proposed for it. However, a critical consideration of the matter of the area is complicated, since the exact mechanisms are very difficult to explore and clarify, and most publications are of an empirical and "phenomenological" nature, reporting a dependence of the antiviral action on illumination, or a correlation of activity with the photophysical properties of the substances. Of particular interest is substance-assisted photogeneration of highly reactive singlet oxygen (1O2). The damaging action of 1O2 on the lipids of the viral envelope can probably lead to a loss of the ability of the lipid bilayer of enveloped viruses to fuse with the lipid membrane of the host cell. Thus, lipid bilayer-affine 1O2 photosensitizers have prospects as broad-spectrum antivirals against enveloped viruses. In this short review, we want to point out the main types of antiviral photosensitizers with potential affinity to the lipid bilayer and summarize the data on new compounds over the past three years. Further understanding of the data in the field will spur a targeted search for substances with antiviral activity against enveloped viruses among photosensitizers able to bind to the lipid membranes.


Subject(s)
Antiviral Agents , Membrane Lipids/metabolism , Photosensitizing Agents , Viral Envelope/metabolism , Virus Diseases , Viruses/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Humans , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacokinetics , Photosensitizing Agents/therapeutic use , Singlet Oxygen , Virus Diseases/drug therapy , Virus Diseases/metabolism
15.
Molecules ; 26(8)2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1302417

ABSTRACT

Two new ultra-high performance liquid chromatography (UHPLC) methods for analyzing 21 selected antivirals and their metabolites were optimized, including sample preparation step, LC separation conditions, and tandem mass spectrometry detection. Micro-solid phase extraction in pipette tips was used to extract antivirals from the biological material of Hanks balanced salt medium of pH 7.4 and 6.5. These media were used in experiments to evaluate the membrane transport of antiviral drugs. Challenging diversity of physicochemical properties was overcome using combined sorbent composed of C18 and ion exchange moiety, which finally allowed to cover the whole range of tested antivirals. For separation, reversed-phase (RP) chromatography and hydrophilic interaction liquid chromatography (HILIC), were optimized using extensive screening of stationary and mobile phase combinations. Optimized RP-UHPLC separation was carried out using BEH Shield RP18 stationary phase and gradient elution with 25 mmol/L formic acid in acetonitrile and in water. HILIC separation was accomplished with a Cortecs HILIC column and gradient elution with 25 mmol/L ammonium formate pH 3 and acetonitrile. Tandem mass spectrometry (MS/MS) conditions were optimized in both chromatographic modes, but obtained results revealed only a little difference in parameters of capillary voltage and cone voltage. While RP-UHPLC-MS/MS exhibited superior separation selectivity, HILIC-UHPLC-MS/MS has shown substantially higher sensitivity of two orders of magnitude for many compounds. Method validation results indicated that HILIC mode was more suitable for multianalyte methods. Despite better separation selectivity achieved in RP-UHPLC-MS/MS, the matrix effects were noticed while using both chromatographic modes leading to signal enhancement in RP and signal suppression in HILIC.


Subject(s)
Antiviral Agents/pharmacokinetics , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Solid Phase Microextraction , Tandem Mass Spectrometry , Antiviral Agents/chemistry , Drug Monitoring , Humans , Reproducibility of Results
16.
CPT Pharmacometrics Syst Pharmacol ; 10(9): 973-982, 2021 09.
Article in English | MEDLINE | ID: covidwho-1293320

ABSTRACT

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs. Continuous development and expansion are feasible with the public availability of this database.


Subject(s)
Antiviral Agents/pharmacology , Databases, Pharmaceutical , SARS-CoV-2/drug effects , Antiviral Agents/pharmacokinetics , Drug Repositioning/methods , Humans
17.
Drug Deliv ; 28(1): 1150-1165, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1271847

ABSTRACT

The objective of this paper is to confine piperine, a poor oral bioavailable herbal drug into bile salt based nano vesicles for improving its aqueous solubility, hence, its therapeutic activity. Piperine-loaded bilosomes were fabricated adopting thin film hydration technique according to 32.21 full factorial design to investigate the impact of different formulation variables on the characters of bilosomes: entrapment efficiency (EE%), particle size, and % of drug released post 8 h (Q8hr). The selected optimum formula was F2 (enclosing 1% bile salt, brij72 as a surfactant, and ratio of surfactant:cholesterol was 9:1) with desirability value 0.801, exhibiting high EE% (97.2 ± 0.8%) nanosized spherical vesicles (220.2 ± 20.5 nm) and Q8hr (88.2%±5.6). The superiority of the optimized formula (F2) over the drug suspension was revealed via ex vivo permeation study, also pharmacokinetic study denoted to the boosted oral bioavailability of piperine-loaded bilosome compared to piperine suspension. Moreover, antiviral activity and safety margin of F2 was significantly higher than that of the drug suspension. The ability of piperine to interact with the key amino acids in the receptor binding domain 4L3N as indicated by its docking configuration, rationalized its observed activity. Furthermore, F2 significantly reduce oxidant markers, inflammatory cytokines in MERS-CoV-infected mice. Hence, bilosomes can be considered as a carrier of choice for piperine with potential antiviral and anti-inflammatory activities.


Subject(s)
Alkaloids , Benzodioxoles , Bile Acids and Salts/pharmacokinetics , Drug Delivery Systems/methods , Middle East Respiratory Syndrome Coronavirus/drug effects , Piperidines , Polyunsaturated Alkamides , Administration, Oral , Alkaloids/administration & dosage , Alkaloids/pharmacokinetics , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Benzodioxoles/administration & dosage , Benzodioxoles/pharmacokinetics , Biological Availability , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Drug Liberation , Liposomes , Mice , Molecular Docking Simulation , Nanostructures , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Plants, Medicinal , Polyunsaturated Alkamides/administration & dosage , Polyunsaturated Alkamides/pharmacokinetics , Surface-Active Agents/pharmacokinetics
18.
Future Med Chem ; 13(17): 1435-1450, 2021 09.
Article in English | MEDLINE | ID: covidwho-1282696

ABSTRACT

The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease. To identify these molecules, we followed a combinatorial structure-based strategy, which includes high-throughput virtual screening, molecular docking and WaterMap calculations. The study was carried out using Protein Data Bank structures 5R82 and 6Y2G. DrugBank, Enamine, Natural product and Specs databases, along with a few known antiviral drugs, were used for the screening. WaterMap analysis aided in the recognition of high-potential molecules that can efficiently displace binding-site waters. This study may help the discovery and development of antiviral drugs against SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Binding Sites/drug effects , Catalysis , Computer Simulation , Databases, Factual , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , Molecular Structure , Protease Inhibitors/pharmacokinetics , Thermodynamics , Water/chemistry
19.
J Mol Recognit ; 34(10): e2918, 2021 10.
Article in English | MEDLINE | ID: covidwho-1270481

ABSTRACT

The novel coronavirus Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) or COVID-19 has caused a worldwide pandemic. The fatal virus has affected the health of human beings as well as the socio-economic situation all over the world. To date, no concrete medicinal solution has been proposed to combat the viral infection, calling for an urgent, strategic, and cost-effective drug development approach that may be achievable by applying targeted computational and virtual screening protocols. Immunity is the body's natural defense against disease-causing pathogens, which can be boosted by consuming plant-based or natural food products. Active constituents derived from natural sources also scavenge the free radicals and have anti-inflammatory activities. Herbs and spices have been used for various medicinal purposes. In this study, 2,96 365 natural and synthetic derivatives (ligands) belonging to 102 classes of compounds were obtained from PubChem and assessed on Lipinski's parameters for their potential bioavailability. Out of all the derivatives, 3254 obeyed Lipinski's rule and were virtually screened. The 115 top derivatives were docked against SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-HKV1 main proteases (Mpro s) as receptors using AutoDock Vina, AutoDock, and iGEMDOCK 2.1. The lowest binding energy was exhibited by ligands 2 and 6 against all the four Mpro s. The molecular dynamic simulation was also performed with ligand 6 using the GROMACS package. Good bioactivity scores, absorption, distribution, metabolism, excretion, and toxicity profile and drug-like pharmacokinetic parameters were also obtained. Hydroxychloroquine was used as the control drug.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Blood-Brain Barrier/drug effects , Computer Simulation , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation
20.
PLoS One ; 16(6): e0248479, 2021.
Article in English | MEDLINE | ID: covidwho-1266543

ABSTRACT

The Coronavirus disease (COVID-19) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagious disease. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific antivirals and immunomodulators. Ayurvedic Rasayana therapy has been traditionally used in India for its immunomodulatory and adaptogenic effects, and more recently has been included as therapeutic adjuvant for several maladies. Amongst several others, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) play an important role in Rasayana therapy. The objective of this study was to explore the immunomodulatory and anti SARS-CoV2 potential of phytoconstituents from Ashwagandha, Guduchi and Shatavari using network pharmacology and docking. The plant extracts were prepared as per ayurvedic procedures and a total of 31 phytoconstituents were identified using UHPLC-PDA and mass spectrometry studies. To assess the immunomodulatory potential of these phytoconstituents an in-silico network pharmacology model was constructed. The model predicts that the phytoconstituents possess the potential to modulate several targets in immune pathways potentially providing a protective role. To explore if these phytoconstituents also possess antiviral activity, docking was performed with the Spike protein, Main Protease and RNA dependent RNA polymerase of the virus. Interestingly, several phytoconstituents are predicted to possess good affinity for the three targets, suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would not be adverse herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals as therapeutic adjuvants in the management of COVID-19 following rigorous experimental validation.


Subject(s)
Antiviral Agents/metabolism , Asparagus Plant/chemistry , COVID-19/metabolism , Immunologic Factors/metabolism , Molecular Docking Simulation/methods , Plant Extracts/metabolism , SARS-CoV-2/enzymology , Tinospora/chemistry , Withania/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Herb-Drug Interactions , Humans , Immunologic Factors/pharmacokinetics , India , Medicine, Ayurvedic/methods , Phytotherapy/methods , Plant Extracts/pharmacokinetics , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism
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