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1.
Antimicrob Agents Chemother ; 66(10): e0063222, 2022 10 18.
Article in English | MEDLINE | ID: covidwho-2019711

ABSTRACT

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.


Subject(s)
Antiviral Agents , COVID-19 , Indazoles , Triazines , Adult , Humans , Administration, Oral , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Area Under Curve , COVID-19/drug therapy , Cytochrome P-450 CYP3A , Dose-Response Relationship, Drug , Double-Blind Method , Enzyme Inhibitors , Healthy Volunteers , Midazolam/therapeutic use , Peptide Hydrolases , Protease Inhibitors , SARS-CoV-2 , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Triazines/pharmacokinetics , Triazines/therapeutic use , Triazoles/pharmacokinetics , Triazoles/therapeutic use
2.
Int J Mol Sci ; 23(8)2022 Apr 09.
Article in English | MEDLINE | ID: covidwho-1785748

ABSTRACT

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.


Subject(s)
COVID-19 , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Pandemics , SARS-CoV-2 , Theophylline/pharmacology , Theophylline/therapeutic use
3.
Int J Pharm ; 620: 121739, 2022 May 25.
Article in English | MEDLINE | ID: covidwho-1783428

ABSTRACT

As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospitalized patients due to intravenous administration, there is an urgent need of effective oral antiviral formulations to be used at early stage of infection in an outpatient setting. The present paper reports on the comparative pharmacokinetics of the electrospun nanofiber remdesivir/sulfobutyl ether beta-cyclodextrin formulation after intravenous and buccal administration. It was postulated that oral transmucosal administration avoids remdesivir from metabolic transformation and intact remdesivir can be detected in plasma, but only the active metabolite GS-441524 could be experimentally detected at a significantly lower plasma level, than that provided by the intravenous route. In buccally treated animals, the metabolite GS-441524 appeared only at 1 h after treatment, while in intravenously treated animals, GS-441524 was possible to quantify even at the first time-point of blood collection. Further optimization of formulation is required to improve pharmacokinetics of remdesivir-sulfobutyl ether beta-cyclodextrin formulation upon buccal administration.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Administration, Buccal , Administration, Intravenous , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , COVID-19/drug therapy , Furans , Humans , Pyrroles , Rabbits , Triazines
4.
Clin Pharmacol Ther ; 112(1): 101-111, 2022 07.
Article in English | MEDLINE | ID: covidwho-1777543

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double-blind, placebo-controlled, phase I study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a three-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well-tolerated. Nirmatrelvir exposure and half-life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5-day regimen would significantly decrease viral load in SARS-CoV-2-infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials' initiation (NCT04756531).


Subject(s)
COVID-19 , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Humans , Lactams , Leucine , Nitriles , Proline , Ritonavir , SARS-CoV-2
5.
Bioengineered ; 12(1): 2274-2287, 2021 12.
Article in English | MEDLINE | ID: covidwho-1769071

ABSTRACT

Xuebijing Injection have been found to improve the clinical symptoms of COVID-19 and alleviate disease severity, but the mechanisms are currently unclear. This study aimed to investigate the potential molecular targets and mechanisms of the Xuebijing injection in treating COVID-19 via network pharmacology and molecular docking analysis. The main active ingredients and therapeutic targets of the Xuebijing injection, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, and GeneCard databases. According to the 'Drug-Ingredients-Targets-Disease' network built by STRING and Cytoscape, AKT1 was identified as the core target, and baicalein, luteolin, and quercetin were identified as the active ingredients of the Xuebijing injection in connection with AKT1. R language was used for enrichment analysis that predict the mechanisms by which the Xuebijing injection may inhibit lipopolysaccharide-mediated inflammatory response, modulate NOS activity, and regulate the TNF signal pathway by affecting the role of AKT1. Based on the results of network pharmacology, a molecular docking was performed with AKT1 and the three active ingredients, the results indicated that all three active ingredients could stably bind with AKT1. These findings identify potential molecular mechanisms by which Xuebijing Injection inhibit COVID-19 by acting on AKT1.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/metabolism , Drugs, Chinese Herbal/administration & dosage , SARS-CoV-2 , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biomedical Engineering , Drugs, Chinese Herbal/pharmacokinetics , Drugs, Chinese Herbal/pharmacology , Flavanones/administration & dosage , Humans , Injections , Luteolin/administration & dosage , Molecular Docking Simulation , Pandemics , Protein Binding , Protein Interaction Maps , Proto-Oncogene Proteins c-akt/chemistry , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Quercetin/administration & dosage , Signal Transduction/drug effects
7.
Comput Math Methods Med ; 2022: 9604456, 2022.
Article in English | MEDLINE | ID: covidwho-1704361

ABSTRACT

OBJECTIVE: To investigate the potential pharmacological value of extracts from honeysuckle on patients with mild coronavirus disease 2019 (COVID-19) infection. METHODS: The active components and targets of honeysuckle were screened by Traditional Chinese Medicine Database and Analysis Platform (TCMSP). SwissADME and pkCSM databases predict pharmacokinetics of ingredients. The Gene Expression Omnibus (GEO) database collected transcriptome data for mild COVID-19. Data quality control, differentially expressed gene (DEG) identification, enrichment analysis, and correlation analysis were implemented by R toolkit. CIBERSORT evaluated the infiltration of 22 immune cells. RESULTS: The seven active ingredients of honeysuckle had good oral absorption and medicinal properties. Both the active ingredient targets of honeysuckle and differentially expressed genes of mild COVID-19 were significantly enriched in immune signaling pathways. There were five overlapping immunosignature genes, among which RELA and MAP3K7 expressions were statistically significant (P < 0.05). Finally, immune cell infiltration and correlation analysis showed that RELA, MAP3K7, and natural killer (NK) cell are with highly positive correlation and highly negatively correlated with hematopoietic stem cells. CONCLUSION: Our analysis suggested that honeysuckle extract had a safe and effective protective effect against mild COVID-19 by regulating a complex molecular network. The main mechanism was related to the proportion of infiltration between NK cells and hematopoietic stem cells.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal/therapeutic use , Lonicera , Phytotherapy , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/genetics , COVID-19/immunology , Computational Biology , Databases, Pharmaceutical/statistics & numerical data , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacokinetics , Gene Expression/drug effects , Gene Ontology , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/immunology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lonicera/chemistry , Medicine, Chinese Traditional , Pandemics , SARS-CoV-2/drug effects
8.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1684525

ABSTRACT

Pneumonia, especially corona virus disease 2019 (COVID-19), can lead to serious acute lung injury, acute respiratory distress syndrome, multiple organ failure and even death. Thus it is an urgent task for developing high-efficiency, low-toxicity and targeted drugs according to pathogenesis of coronavirus. In this paper, a novel disease-related compound identification model-based capsule network (CapsNet) is proposed. According to pneumonia-related keywords, the prescriptions and active components related to the pharmacological mechanism of disease are collected and extracted in order to construct training set. The features of each component are extracted as the input layer of capsule network. CapsNet is trained and utilized to identify the pneumonia-related compounds in Qingre Jiedu injection. The experiment results show that CapsNet can identify disease-related compounds more accurately than SVM, RF, gcForest and forgeNet.


Subject(s)
Antiviral Agents , COVID-19 , Drug Delivery Systems , Models, Biological , Neural Networks, Computer , SARS-CoV-2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , COVID-19/metabolism , Humans
9.
J Am Chem Soc ; 144(7): 2905-2920, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1683927

ABSTRACT

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Microsomes, Liver/metabolism , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/enzymology , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacokinetics , Vero Cells
10.
Eur J Med Res ; 27(1): 21, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1666676

ABSTRACT

The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for steroids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Ivermectin/adverse effects , Ivermectin/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Clinical Trials as Topic , Humans , Ivermectin/administration & dosage , Ivermectin/pharmacokinetics , Pre-Exposure Prophylaxis/methods
11.
Antiviral Res ; 198: 105246, 2022 02.
Article in English | MEDLINE | ID: covidwho-1639070

ABSTRACT

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung Diseases, Interstitial/prevention & control , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Administration, Cutaneous , Alanine/administration & dosage , Alanine/pharmacokinetics , Alanine/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Disease Models, Animal , Female , Lung/pathology , Lung/virology , Macaca mulatta , Male , Viral Load/drug effects , Virus Replication/drug effects
12.
Bioengineered ; 13(2): 3350-3361, 2022 02.
Article in English | MEDLINE | ID: covidwho-1632167

ABSTRACT

The COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (Mpro) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, Mpro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 Mpro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of Mpro with Boceprevir, Apigenin, Apigenin 7-glucoside-4'-p-coumarate, Apigenin 7-glucoside-4'-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be -6.6, -7.2, -8.8, -8.7 and -8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4'-p-coumarate is the best candidate for SARS-CoV-2 Mpro inhibition.


Subject(s)
Antiviral Agents/pharmacology , Apigenin/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Apigenin/chemistry , Apigenin/pharmacokinetics , Bioengineering , COVID-19/virology , Computer Simulation , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Evaluation, Preclinical , Glucosides/chemistry , Glucosides/pharmacokinetics , Glucosides/pharmacology , Humans , Molecular Docking Simulation , Phytotherapy , Protein Domains , SARS-CoV-2/genetics
13.
Molecules ; 27(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1624914

ABSTRACT

A novel series of 1-aryl-N-[4-phenyl-5-(arylazo)thiazol-2-yl)methanimines has been synthesized via the condensation of 2-amino-4-phenyl-5-arylazothiazole with various aromatic aldehydes. The synthesized imines were characterized by spectroscopic techniques, namely 1H and 13C-NMR, FTIR, MS, and Elemental Analysis. A molecular comparative docking study for 3a-f was calculated, with reference to two approved drugs, Molnupiravir and Remdesivir, using 7BQY (Mpro; PDB code 7BQY; resolution: 1.7 A°) under identical conditions. The binding scores against 7BQY were in the range of -7.7 to -8.7 kcal/mol for 3a-f. The high scores of the compounds indicated an enhanced binding affinity of the molecules to the receptor. This is due to the hydrophobic interactions and multi-hydrogen bonds between 3a-f ligands and the receptor's active amino acid residues. The main aim of using in silco molecular docking was to rank 3a-f with respect to the approved drugs, Molnupiravir and Remdesivir, using free energy methods as greener pastures. A further interesting comparison presented the laydown of the ligands before and after molecular docking. These results and other supporting statistical analyses suggested that ligands 3a-f deserve further investigation in the context of potential therapeutic agents for COVID-19. Free-cost, PASS, SwissADME, and Way2drug were used in this research paper to determine the possible biological activities and cytotoxicity of 3a-f.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Imines/chemistry , Thiazoles/chemistry , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/analogs & derivatives , Alanine/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Computer Simulation , Coronavirus 3C Proteases/chemistry , Cytidine/analogs & derivatives , Cytidine/chemistry , Hydroxylamines/chemistry , Imines/chemical synthesis , Imines/pharmacokinetics , Imines/toxicity , Molecular Docking Simulation , SARS-CoV-2/drug effects , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Thiazoles/toxicity
14.
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
15.
Int J Antimicrob Agents ; 59(2): 106516, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1611755

ABSTRACT

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Ivermectin/pharmacokinetics , SARS-CoV-2/drug effects , Adult , Antiparasitic Agents/blood , Antiparasitic Agents/pharmacokinetics , Antiparasitic Agents/pharmacology , Antiviral Agents/blood , Antiviral Agents/pharmacology , COVID-19/blood , COVID-19/virology , Double-Blind Method , Drug Repositioning , Female , Humans , Ivermectin/blood , Ivermectin/pharmacology , Male , Middle Aged , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , Treatment Outcome , Viral Load/drug effects
16.
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
17.
Sci Transl Med ; 14(633): eabl8282, 2022 Feb 23.
Article in English | MEDLINE | ID: covidwho-1598975

ABSTRACT

Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Chlorocebus aethiops , Humans , Primates , SARS-CoV-2 , Viral Load
18.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1598417

ABSTRACT

The outbreak of COVID-19 caused by SARS-coronavirus (CoV)-2 has made millions of deaths since 2019. Although a variety of computational methods have been proposed to repurpose drugs for treating SARS-CoV-2 infections, it is still a challenging task for new viruses, as there are no verified virus-drug associations (VDAs) between them and existing drugs. To efficiently solve the cold-start problem posed by new viruses, a novel constrained multi-view nonnegative matrix factorization (CMNMF) model is designed by jointly utilizing multiple sources of biological information. With the CMNMF model, the similarities of drugs and viruses can be preserved from their own perspectives when they are projected onto a unified latent feature space. Based on the CMNMF model, we propose a deep learning method, namely VDA-DLCMNMF, for repurposing drugs against new viruses. VDA-DLCMNMF first initializes the node representations of drugs and viruses with their corresponding latent feature vectors to avoid a random initialization and then applies graph convolutional network to optimize their representations. Given an arbitrary drug, its probability of being associated with a new virus is computed according to their representations. To evaluate the performance of VDA-DLCMNMF, we have conducted a series of experiments on three VDA datasets created for SARS-CoV-2. Experimental results demonstrate that the promising prediction accuracy of VDA-DLCMNMF. Moreover, incorporating the CMNMF model into deep learning gains new insight into the drug repurposing for SARS-CoV-2, as the results of molecular docking experiments reveal that four antiviral drugs identified by VDA-DLCMNMF have the potential ability to treat SARS-CoV-2 infections.


Subject(s)
Antiviral Agents , COVID-19 , Deep Learning , Drug Repositioning , Molecular Docking Simulation , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , COVID-19/metabolism , Humans , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism
19.
Viruses ; 14(1)2021 12 31.
Article in English | MEDLINE | ID: covidwho-1580398

ABSTRACT

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell-cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.


Subject(s)
Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Biological Availability , Cell Line , Cell Survival/drug effects , Coronavirus/classification , Coronavirus/drug effects , HIV Fusion Inhibitors/chemistry , HIV Fusion Inhibitors/pharmacokinetics , HIV Fusion Inhibitors/pharmacology , Humans , Protein Binding , Rats , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors
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