Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 31
Filter
1.
BMC Pharmacol Toxicol ; 22(1): 61, 2021 10 21.
Article in English | MEDLINE | ID: covidwho-1477468

ABSTRACT

BACKGROUND: The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10 years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19. METHODS: We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity. RESULTS: Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties. CONCLUSION: In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.


Subject(s)
Antiviral Agents/toxicity , COVID-19/drug therapy , Drug Discovery , Drug Repositioning , Animals , Antiviral Agents/adverse effects , Captopril/therapeutic use , Cardiotoxins/toxicity , Catechols/therapeutic use , Computational Biology , Cytochrome P-450 Enzyme System/metabolism , Drug Discovery/methods , Humans , Indomethacin/therapeutic use , Linezolid/therapeutic use , Liver/drug effects , Mice , Models, Biological , Nitriles/therapeutic use , Rats , Reproduction/drug effects , Software , Valproic Acid/therapeutic use
2.
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
3.
J Chem Inf Model ; 61(9): 4125-4130, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1404871

ABSTRACT

A recent publication in Science has proposed that cationic amphiphilic drugs repurposed for COVID-19 typically use phosholipidosis as their antiviral mechanism of action in cells but will have no in vivo efficacy. On the contrary, our viewpoint, supported by additional experimental data for similar cationic amphiphilic drugs, indicates that many of these molecules have both in vitro and in vivo efficacy with no reported phospholipidosis, and therefore, this class of compounds should not be avoided but further explored, as we continue the search for broad spectrum antivirals.


Subject(s)
COVID-19 , Lipidoses , Pharmaceutical Preparations , Antiviral Agents/toxicity , Humans , Lipidoses/drug therapy , Phospholipids , SARS-CoV-2
4.
Science ; 373(6554): 541-547, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1334531

ABSTRACT

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Lipidoses/chemically induced , Phospholipids/metabolism , SARS-CoV-2/drug effects , A549 Cells , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , COVID-19/virology , Cations , Chlorocebus aethiops , Dose-Response Relationship, Drug , Female , Humans , Mice , Microbial Sensitivity Tests , SARS-CoV-2/physiology , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacology , Surface-Active Agents/toxicity , Vero Cells , Virus Replication/drug effects
5.
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
6.
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
7.
Phytomedicine ; 87: 153591, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1240546

ABSTRACT

BACKGROUND: The outbreak of coronavirus (SARS-CoV-2) disease caused more than 100,000,000 people get infected and over 2,200,000 people being killed worldwide. However, the current developed vaccines or drugs may be not effective in preventing the pandemic of COVID-19 due to the mutations of coronavirus and the severe side effects of the newly developed vaccines. Chinese herbal medicines and their active components play important antiviral activities. Corilagin exhibited antiviral effect on human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV). However, whether it blocks the interaction between SARS-CoV-2 RBD and hACE2 has not been elucidated. PURPOSE: To characterize an active compound, corilagin derived from Phyllanthus urinaria as potential SARS-CoV-2 entry inhibitors for its possible preventive application in daily anti-virus hygienic products. METHODS: Computational docking coupled with bio-layer interferometry, BLI were adopted to screen more than 1800 natural compounds for the identification of SARS-CoV-2 spike-RBD inhibitors. Corilagin was confirmed to have a strong binding affinity with SARS-CoV-2-RBD or human ACE2 (hACE2) protein by the BLI, ELISA and immunocytochemistry (ICC) assay. Furthermore, the inhibitory effect of viral infection of corilagin was assessed by in vitro pseudovirus system. Finally, the toxicity of corilagin was examined by using MTT assay and maximal tolerated dose (MTD) studies in C57BL/6 mice. RESULTS: Corilagin preferentially binds to a pocket that contains residues Cys 336 to Phe 374 of spike-RBD with a relatively low binding energy of -9.4 kcal/mol. BLI assay further confirmed that corilagin exhibits a relatively strong binding affinity to SARS-CoV-2-RBD and hACE2 protein. In addition, corilagin dose-dependently blocks SARS-CoV-2-RBD binding and abolishes the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of SARS-CoV-2 virus in human host cells. Finally, in vivo studies revealed that up to 300 mg/kg/day of corilagin was safe in C57BL/6 mice. Our findings suggest that corilagin could be a safe and potential antiviral agent against the COVID-19 acting through the blockade of the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors. CONCLUSION: Corilagin could be considered as a safe and environmental friendly anti-SARS-CoV-2 agent for its potential preventive application in daily anti-virus hygienic products.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Glucosides/pharmacology , Host-Pathogen Interactions/drug effects , Hydrolyzable Tannins/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , COVID-19 , Epstein-Barr Virus Infections/drug therapy , Glucosides/chemistry , Glucosides/toxicity , HEK293 Cells , Humans , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/toxicity , Lentivirus Infections/drug therapy , Male , Maximum Tolerated Dose , Mice, Inbred C57BL , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus/chemistry
8.
Eur J Med Chem ; 220: 113467, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1184952

ABSTRACT

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC50 ≤ 20 µM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC50 values in low micromolar range, although accompanied by commensurate cytotoxicity.


Subject(s)
Antiviral Agents/pharmacology , DNA Viruses/drug effects , Nucleosides/pharmacology , Oxazines/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/toxicity , Cell Line, Tumor , Chlorocebus aethiops , Dogs , Humans , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/toxicity , Oxazines/chemical synthesis , Oxazines/toxicity , Structure-Activity Relationship , Vero Cells , Virus Replication/drug effects
9.
Biomolecules ; 11(3)2021 03 19.
Article in English | MEDLINE | ID: covidwho-1148287

ABSTRACT

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = -8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = -6.49 kcal/mol), and nsp10 (ΔG = -9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = -7.99 kcal/mol), spike glycoproteins (ΔG = -6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = -8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.


Subject(s)
Alkaloids/chemistry , Antiviral Agents/chemistry , Coronavirus Nucleocapsid Proteins/chemistry , Porifera/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/toxicity , Blood-Brain Barrier , Crystallography, X-Ray , Ligands , Membrane Glycoproteins/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Phosphoproteins/chemistry , Protease Inhibitors/chemistry , Rats , Software , Viral Proteases/chemistry
10.
Molecules ; 26(5)2021 Mar 07.
Article in English | MEDLINE | ID: covidwho-1136523

ABSTRACT

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.


Subject(s)
Methyltransferases/antagonists & inhibitors , Methyltransferases/metabolism , RNA Helicases/antagonists & inhibitors , RNA Helicases/metabolism , SARS-CoV-2/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Biological Availability , COVID-19/drug therapy , Computational Biology/methods , Databases, Chemical , Drug Design , Humans , Hydrogen Bonding , Methyltransferases/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals/chemistry , Phytochemicals/metabolism , Plants, Medicinal/chemistry , Protein Binding , Protein Domains/drug effects , Pyrimidines/chemistry , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/toxicity , RNA Helicases/chemistry , Structure-Activity Relationship , Thermodynamics , Viral Nonstructural Proteins/chemistry
11.
Sci Total Environ ; 776: 145740, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1082435

ABSTRACT

Antiviral drugs have been used to treat the ever-growing number of coronavirus disease, 2019 (COVID-19) patients. Consequently, unprecedented amounts of such drug residues discharging into ambient waters raise concerns on the potential ecotoxicological effects to aquatic lives, as well as development of antiviral drug-resistance in wildlife. Here, we estimated the occurrence, fate and ecotoxicological risk of 11 therapeutic agents suggested as drugs for COVID-19 treatment and their 13 metabolites in wastewater and environmental waters, based on drug consumption, physical-chemical property, and ecotoxicological and pharmacological data for the drugs, with the aid of quantitative structure-activity relationship (QSAR) modelling. Our results suggest that the removal efficiencies at conventional wastewater treatment plants will remain low (<20%) for half of the substances, and consequently, high drug residues (e.g. 7402 ng/L ribavirin, 4231 ng/L favipiravir, 730 ng/L lopinavir, 319 ng/L remdesivir; each combined for both unchanged forms and metabolites; and when each drug is administered to 100 patients out of 100,000 populations on a day) can be present in secondary effluents and persist in the environmental waters. Ecotoxicological risk in receiving river waters can be high (risk quotient >1) by a use of favipiravir, lopinavir, umifenovir and ritonavir, and medium (risk quotient >0.1) by a use of chloroquine, hydroxychloroquine, remdesivir, and ribavirin, while the risk will remain low (risk quotient <0.1) for dexamethasone and oseltamivir. The potential of wild animals acquiring antiviral drug resistance was estimated to be low. Our prediction suggests a pressing need for proper usage and waste management of antiviral drugs as well as for improving removal efficiencies of drug residues in wastewater.


Subject(s)
COVID-19 , Coronavirus , Animals , Antiviral Agents/toxicity , COVID-19/drug therapy , Humans , SARS-CoV-2
12.
J Hazard Mater ; 405: 124043, 2021 03 05.
Article in English | MEDLINE | ID: covidwho-1065326

ABSTRACT

In this review, we present the environmental perspectives of the viruses and antiviral drugs related to SARS-CoV-2. The present review paper discusses occurrence, fate, transport, susceptibility, and inactivation mechanisms of viruses in the environment as well as environmental occurrence and fate of antiviral drugs, and prospects (prevalence and occurrence) of antiviral drug resistance (both antiviral drug resistant viruses and antiviral resistance in the human). During winter, the number of viral disease cases and environmental occurrence of antiviral drug surge due to various biotic and abiotic factors such as transmission pathways, human behaviour, susceptibility, and immunity as well as cold climatic conditions. Adsorption and persistence critically determine the fate and transport of viruses in the environment. Inactivation and disinfection of virus include UV, alcohol, and other chemical-base methods but the susceptibility of virus against these methods varies. Wastewater treatment plants (WWTPs) are major reserviors of antiviral drugs and their metabolites and transformation products. Ecotoxicity of antiviral drug residues against aquatic organisms have been reported, however more threatening is the development of antiviral resistance, both in humans and in wild animal reservoirs. In particular, emergence of antiviral drug-resistant viruses via exposure of wild animals to high loads of antiviral residues during the current pandemic needs further evaluation.


Subject(s)
Antiviral Agents , Drug Resistance, Viral/drug effects , Environmental Microbiology , Environmental Pollutants , SARS-CoV-2 , Virus Inactivation , Adsorption , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Aquatic Organisms/drug effects , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/etiology , Ecotoxicology , Environmental Pollutants/chemistry , Environmental Pollutants/therapeutic use , Environmental Pollutants/toxicity , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Seasons , Virus Inactivation/drug effects , Virus Inactivation/radiation effects , Water Purification
13.
J Ethnopharmacol ; 273: 113871, 2021 Jun 12.
Article in English | MEDLINE | ID: covidwho-1042531

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Reduning injection (RDNI) is a patented Traditional Chinese medicine that contains three Chinese herbal medicines, respectively are the dry aboveground part of Artemisia annua L., the flower of Lonicera japonica Thunb., and the fruit Gardenia jasminoides J.Ellis. RDNI has been recommended for treating Coronavirus Disease 2019 (COVID-19) in the "New Coronavirus Pneumonia Diagnosis and Treatment Plan". AIM OF THE STUDY: To elucidate and verify the underlying mechanisms of RDNI for the treatment of COVID-19. METHODS: This study firstly performed anti-SARS-CoV-2 experiments in Vero E6 cells. Then, network pharmacology combined with molecular docking was adopted to explore the potential mechanisms of RDNI in the treatment for COVID-19. After that, western blot and a cytokine chip were used to validate the predictive results. RESULTS: We concluded that half toxic concentration of drug CC50 (dilution ratio) = 1:1280, CC50 = 2.031 mg crude drugs/mL (0.047 mg solid content/mL) and half effective concentration of drug (EC50) (diluted multiples) = 1:25140.3, EC50 = 103.420 µg crude drugs/mL (2.405 µg solid content/mL). We found that RDNI can mainly regulate targets like carbonic anhydrases (CAs), matrix metallopeptidases (MMPs) and pathways like PI3K/AKT, MAPK, Forkhead box O s and T cell receptor signaling pathways to reduce lung damage. We verified that RDNI could effectively inhibit the overexpression of MAPKs, PKC and p65 nuclear factor-κB. The injection could also affect cytokine levels, reduce inflammation and display antipyretic activity. CONCLUSION: RDNI can regulate ACE2, Mpro and PLP in COVID-19. The underlying mechanisms of RDNI in the treatment for COVID-19 may be related to the modulation of the cytokine levels and inflammation and its antipyretic activity by regulating the expression of MAPKs, PKC and p65 nuclear factor NF-κB.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , Cell Line, Transformed , Chlorocebus aethiops , Computational Biology , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/metabolism , Cytokines/metabolism , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/toxicity , Humans , Medicine, Chinese Traditional/methods , Molecular Docking Simulation , Protein Array Analysis , SARS-CoV-2/drug effects , Signal Transduction/drug effects , Vero Cells
14.
Food Addit Contam Part A Chem Anal Control Expo Risk Assess ; 38(1): 148-159, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1024072

ABSTRACT

Coix seed is an important food and traditional Chinese medicine in China and other Asian countries. Notably, coix seed is currently being used as a traditional medicine for the treatment of COVID-19 in China. However, coix seeds are generally contaminated by mycotoxins, and this risk cannot be ignored. In this paper, we developed a method that involves direct extraction and UHPLC-HRMS analysis for the simultaneous detection of 24 mycotoxins in coix seeds. UHPLC-HRMS instrument and data acquisition parameters, and the sample pretreatment were optimised. One-step extraction showed several advantages compared to the three commercial solid-phase extraction clean-up methods, including ease of use, reduced time of sample preparation, low cost, good recovery, and acceptable matrix effect. The method validation results indicate that all mycotoxins have good linearity and sensitivity. Recoveries were between 74.2-101.1%, and RSD ranged from 0.1-5.8%. The LOQs for 24 mycotoxins were in the range of 0.5-100 µg/kg. To survey the contamination levels of these mycotoxins in commercial coix seeds, more than 70 samples were collected from Chinese markets and were analysed using the newly developed method. Zearalenone (positive ratio: 98.7%, range:1.1-1562 µg/kg), deoxynivalenol (positive ratio: 87%, range: 8.4-382.5 µg/kg), nivalenol (positive ratio: 85.7%, range: 26.8-828.2 µg/kg), fumonisin B1 (positive ratio: 84.4%, range:2.5-314.5 µg/kg), fumonisin B2 (positive ratio: 75.3%, range:1.6-72.8 µg/kg), fumonisin B3 (positive ratio: 48%, range:1.0-203.6 µg/kg), aflatoxin B1 (positive ratio: 29.9%, range: 0.39-14.7 µg/kg), sterigmatocystin (positive ratio: 29.9%, range: 1.4-51.6 µg/kg), and tenuazonic acid (positive ratio: 19.5%, range 36.1-105.7 µg/kg) were the most frequent mycotoxin contaminants. These results highlight the importance of routine monitoring and control of mycotoxins in coix seeds.


Subject(s)
COVID-19/drug therapy , Coix/chemistry , Drug Contamination , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/toxicity , Mycotoxins/analysis , Mycotoxins/toxicity , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , China , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/therapeutic use , Humans , Pandemics , Risk Assessment , SARS-CoV-2 , Seeds/chemistry , Solvents , Spectrometry, Mass, Electrospray Ionization/methods
15.
Antimicrob Agents Chemother ; 65(1)2020 12 16.
Article in English | MEDLINE | ID: covidwho-1015593

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.


Subject(s)
Antiviral Agents/pharmacology , Drug Repositioning/methods , Nucleosides/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , Cell Line , Chlorocebus aethiops , Coronavirus OC43, Human/drug effects , Drug Evaluation, Preclinical , Humans , Nucleosides/chemistry , Nucleosides/toxicity , Propanolamines/pharmacology , Sofosbuvir/pharmacology , Vero Cells
16.
Antivir Chem Chemother ; 28: 2040206620983780, 2020.
Article in English | MEDLINE | ID: covidwho-999586

ABSTRACT

BACKGROUND: Gallium has demonstrated strong anti-inflammatory activity in numerous animal studies, and has also demonstrated direct antiviral activity against the influenza A H1N1 virus and the human immunodeficiency virus (HIV). Gallium maltolate (GaM), a small metal-organic coordination complex, has been tested in several Phase 1 clinical trials, in which no dose-limiting or other serious toxicity was reported, even at high daily oral doses for several months at a time. For these reasons, GaM may be considered a potential candidate to treat coronavirus disease 2019 (COVID-19), which is caused by the SARS-CoV-2 virus and can result in severe, sometimes lethal, inflammatory reactions. In this study, we assessed the ability of GaM to inhibit the replication of SARS-CoV-2 in a culture of Vero E6 cells. METHODS: The efficacy of GaM in inhibiting the replication of SARS-CoV-2 was determined in a screening assay using cultured Vero E6 cells. The cytotoxicity of GaM in uninfected cells was determined using the Cell Counting Kit-8 (CCK-8) colorimetric assay. RESULTS: The results showed that GaM inhibits viral replication in a dose-dependent manner, with the concentration that inhibits replication by 50% (EC50) being about 14 µM. No cytotoxicity was observed at concentrations up to at least 200 µM. CONCLUSION: The in vitro activity of GaM against SARS-CoV-2, together with GaM's known anti-inflammatory activity, provide justification for testing GaM in COVID-19 patients.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Organometallic Compounds/pharmacology , Pyrones/pharmacology , SARS-CoV-2/drug effects , Animals , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Iron/metabolism , Organometallic Compounds/therapeutic use , Organometallic Compounds/toxicity , Pyrones/therapeutic use , Pyrones/toxicity , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
17.
Eur J Pharmacol ; 892: 173779, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-959761

ABSTRACT

The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2. NSP15 is an attractive druggable target due to its critical role in SARS-CoV2 replication and virulence in addition to interference with the host immune system. Here in the present study, we integrated the high throughput computational screening and dynamic simulation approach to identify the most promising candidate lead compound against NSP15.5-fluoro-2-oxo-1H-pyrazine-3-carboxamide (favipiravir), (3R,4R, 5R)-3,4-Bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one) remedesivir, 1,3-thiazol-5-ylmethyl N-[(2S,3S, 5S)-3-hydroxy-5-[[(2 S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (ritonavir), ethyl (3R,4R, 5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate (oseltamivir), and (2 S)-N-[(2S,4S, 5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (lopinavir) were chosen as a training set to generate the pharmacophore model. A dataset of ~140,000 compounds library was screened against the designed pharmacophore model and 10 unique compounds were selected that passed successfully through geometry constraints, Lipinski Rule of 5, and ADME/Tox filters along with a strong binding affinity for NSP15 binding cavity. The best fit compound was selected for dynamic simulation to have detailed structural features critical for binding with the NSP15 protein. Given our detailed integrative computational analysis, a Small molecule (3,3-Dimethyl-N-[4-(1-piperidinylcarbonyl) phenyl] butanamide) with drug-like properties and high binding affinity with the NSP15 is proposed as a most promising potential drug against COVID-19. The current computational integrative approach may complement high-throughput screening and the shortlisted small molecule may contribute to selective targeting of NSP15 to stop the replication of SARS-CoV2.


Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , COVID-19/metabolism , Endoribonucleases/metabolism , Piperidines/pharmacology , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Benzamides/pharmacokinetics , Drug Design , Endoribonucleases/chemistry , High-Throughput Screening Assays , Molecular Docking Simulation , Molecular Dynamics Simulation , Piperidines/pharmacokinetics , Viral Nonstructural Proteins/chemistry
18.
J Phys Chem B ; 124(47): 10641-10652, 2020 11 25.
Article in English | MEDLINE | ID: covidwho-943842

ABSTRACT

Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (-59.6 kcal/mol) binds more strongly as compared to compound-8 (-46.3 kcal/mol) and remdesivir (-29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/metabolism , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Enzyme Inhibitors/metabolism , SARS-CoV-2/enzymology , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/toxicity , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacokinetics , Alanine/toxicity , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Caco-2 Cells , Catalytic Domain , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Density Functional Theory , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/toxicity , Humans , Hydrogen Bonding , Models, Chemical , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Thermodynamics
19.
J Microbiol Biotechnol ; 30(12): 1843-1853, 2020 Dec 28.
Article in English | MEDLINE | ID: covidwho-934537

ABSTRACT

COVID-19, caused by the novel coronavirus SARS-CoV-2, has spread globally and caused serious social and economic problems. The WHO has declared this outbreak a pandemic. Currently, there are no approved vaccines or antiviral drugs that prevent SARS-CoV-2 infection. Drugs already approved for clinical use would be ideal candidates for rapid development as COVID-19 treatments. In this work, we screened 1,473 FDA-approved drugs to identify inhibitors of SARS-CoV-2 infection using cell-based assays. The antiviral activity of each compound was measured based on the immunofluorescent staining of infected cells using anti-dsRNA antibody. Twenty-nine drugs among those tested showed antiviral activity against SARS-CoV-2. We report this new list of inhibitors to quickly provide basic information for consideration in developing potential therapies.


Subject(s)
Antiviral Agents/pharmacology , Drug Approval , Drug Repositioning , SARS-CoV-2/drug effects , Antiviral Agents/toxicity , Humans , United States , United States Food and Drug Administration
20.
Bioconjug Chem ; 31(11): 2553-2563, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-872629

ABSTRACT

As a large enveloped RNA virus, coronavirus is of considerable medical and veterinary significance, and anticoronavirus treatment is challenging due to its biodiversity and rapid variability. In this study, Au@Ag nanorods (Au@AgNRs) were successfully synthesized by coating AuNRs with silver and were shown for the first time to have activity against the replication of porcine epidemic diarrhea virus (PEDV). Viral titer analysis demonstrated that Au@AgNRs could inhibit PEDV infection by 4 orders of magnitude at 12 h post-infection, which was verified by viral protein expression analysis. The potential mechanism of action showed that Au@AgNRs could inhibit the entry of PEDV and decrease the mitochondrial membrane potential and caspase-3 activity. Additionally, we demonstrated that a large amount of virus proliferation can cause the generation of reactive oxygen species in cells, and the released Ag+ and exposed AuNRs by Au@AgNRs after the stimulation of reactive oxygen species has superior antiviral activity to ensure long-term inhibition of the PEDV replication cycle. The integrated results support that Au@AgNRs can serve as a potential therapeutic strategy to prevent the replication of coronavirus.


Subject(s)
Gold/chemistry , Gold/pharmacology , Metal Nanoparticles/chemistry , Porcine epidemic diarrhea virus/drug effects , Porcine epidemic diarrhea virus/physiology , Silver/chemistry , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/toxicity , Chlorocebus aethiops , Dose-Response Relationship, Drug , Gold/toxicity , Nanotubes/chemistry , Vero Cells
SELECTION OF CITATIONS
SEARCH DETAIL
...