Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
Sci Rep ; 10(1): 14290, 2020 08 31.
Article in English | MEDLINE | ID: covidwho-738236

ABSTRACT

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Drug Discovery , Pneumonia, Viral/virology , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/diagnosis , Drug Discovery/methods , Humans , Lopinavir/chemistry , Lopinavir/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pandemics , Pneumonia, Viral/diagnosis , Pyrazines/chemistry , Pyrazines/pharmacology , Ritonavir/chemistry , Ritonavir/pharmacology
2.
J Nanosci Nanotechnol ; 20(12): 7311-7323, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-680345

ABSTRACT

We started a study on the molecular docking of six potential pharmacologically active inhibitors compounds that can be used clinically against the COVID-19 virus, in this case, remdesivir, ribavirin, favipiravir, galidesivir, hydroxychloroquine and chloroquine interacting with the main COVID-19 protease in complex with a COVID-19 N3 protease inhibitor. The highest values of affinity energy found in order from highest to lowest were chloroquine (CHL), hydroxychloroquine (HYC), favipiravir (FAV), galidesivir (GAL), remdesivir (REM) and ribavirin (RIB). The possible formation of hydrogen bonds, associations through London forces and permanent electric dipole were analyzed. The values of affinity energy obtained for the hydroxychloroquine ligands was -9.9 kcal/mol and for the chloroquine of -10.8 kcal/mol which indicate that the coupling contributes to an effective improvement of the affinity energies with the protease. Indicating that, the position chosen to make the substitutions may be a pharmacophoric group, and cause changes in the protease.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Adenine/administration & dosage , Adenine/analogs & derivatives , Adenine/chemistry , Adenine/pharmacology , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacology , Amides/administration & dosage , Amides/chemistry , Amides/pharmacology , Antiviral Agents/administration & dosage , Binding Sites , Chloroquine/administration & dosage , Chloroquine/chemistry , Chloroquine/pharmacology , Drug Interactions , Humans , Hydrogen Bonding , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Ligands , Molecular Docking Simulation , Nanotechnology , Pandemics , Protease Inhibitors/administration & dosage , Pyrazines/administration & dosage , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrrolidines/administration & dosage , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Ribavirin/administration & dosage , Ribavirin/chemistry , Ribavirin/pharmacology , Static Electricity
3.
Sci Immunol ; 5(48)2020 06 05.
Article in English | MEDLINE | ID: covidwho-545978

ABSTRACT

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Benzamides/pharmacology , Benzamides/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Pyrazines/pharmacology , Pyrazines/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/metabolism , Aged , Aged, 80 and over , Coronavirus Infections/virology , Critical Illness , Female , Follow-Up Studies , Humans , Inflammation/drug therapy , Inflammation/virology , Interleukin-6/metabolism , Male , Middle Aged , Monocytes/metabolism , Pandemics , Pneumonia, Viral/virology , Prospective Studies , Respiration, Artificial , Treatment Outcome
4.
Int J Mol Sci ; 21(11)2020 May 30.
Article in English | MEDLINE | ID: covidwho-437471

ABSTRACT

The novel coronavirus, COVID-19, caused by SARS-CoV-2, is a global health pandemic that started in December 2019. The effective drug target among coronaviruses is the main protease Mpro, because of its essential role in processing the polyproteins that are translated from the viral RNA. In this study, the bioactivity of some selected heterocyclic drugs named Favipiravir (1), Amodiaquine (2), 2'-Fluoro-2'-deoxycytidine (3), and Ribavirin (4) was evaluated as inhibitors and nucleotide analogues for COVID-19 using computational modeling strategies. The density functional theory (DFT) calculations were performed to estimate the thermal parameters, dipole moment, polarizability, and molecular electrostatic potential of the present drugs; additionally, Mulliken atomic charges of the drugs as well as the chemical reactivity descriptors were investigated. The nominated drugs were docked on SARS-CoV-2 main protease (PDB: 6LU7) to evaluate the binding affinity of these drugs. Besides, the computations data of DFT the docking simulation studies was predicted that the Amodiaquine (2) has the least binding energy (-7.77 Kcal/mol) and might serve as a good inhibitor to SARS-CoV-2 comparable with the approved medicines, hydroxychloroquine, and remdesivir which have binding affinity -6.06 and -4.96 Kcal/mol, respectively. The high binding affinity of 2 was attributed to the presence of three hydrogen bonds along with different hydrophobic interactions between the drug and the critical amino acids residues of the receptor. Finally, the estimated molecular electrostatic potential results by DFT were used to illustrate the molecular docking findings. The DFT calculations showed that drug 2 has the highest of lying HOMO, electrophilicity index, basicity, and dipole moment. All these parameters could share with different extent to significantly affect the binding affinity of these drugs with the active protein sites.


Subject(s)
Antiviral Agents/pharmacology , Cysteine Endopeptidases/chemistry , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Amides/chemistry , Amides/pharmacology , Amodiaquine/chemistry , Amodiaquine/pharmacology , Antiviral Agents/chemistry , Binding Sites , Cysteine Endopeptidases/metabolism , Protease Inhibitors/chemistry , Protein Binding , Pyrazines/chemistry , Pyrazines/pharmacology , Ribavirin/chemistry , Ribavirin/pharmacology , Viral Nonstructural Proteins/metabolism
5.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-165340

ABSTRACT

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus/drug effects , Chloroquine/toxicity , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Intravenous , Alanine/administration & dosage , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Chloroquine/adverse effects , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Immunologic Factors/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Pandemics , Pneumonia, Viral/epidemiology , Pyrazines/pharmacology , Pyrazines/therapeutic use , RNA, Viral/drug effects , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use
7.
Antiviral Res ; 178: 104786, 2020 06.
Article in English | MEDLINE | ID: covidwho-30820

ABSTRACT

An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 µM, 26.63 µM, 2.55 µM and 0.46 µM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 µM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 µM in combination with emetine at 0.195 µM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.


Subject(s)
Antimetabolites/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Emetine/pharmacology , Homoharringtonine/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Virus Replication/drug effects , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/pharmacology , Animals , Betacoronavirus/physiology , Chlorocebus aethiops , Drug Combinations , Epithelial Cells , Humans , Pandemics , Pyrazines/pharmacology , Ribavirin/pharmacology , Vero Cells
8.
Drug Discov Ther ; 14(1): 58-60, 2020.
Article in English | MEDLINE | ID: covidwho-5186

ABSTRACT

The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Discovery , Alanine/analogs & derivatives , Alanine/pharmacology , Amides/pharmacology , Antiviral Agents/chemistry , Betacoronavirus/drug effects , Betacoronavirus/physiology , Chloroquine/pharmacology , Clinical Studies as Topic , Humans , Indoles/pharmacology , Pandemics , Pneumonia, Viral , Pyrazines/pharmacology , Ribonucleotides/pharmacology , Virus Replication/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL