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1.
Int J Antimicrob Agents ; 56(3): 106119, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-690298

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported improved outcomes resulting from an effective reduction or absence of viral load when patients were treated with chloroquine (CQ) or hydroxychloroquine (HCQ). In addition, the effects of these drugs were improved by simultaneous administration of azithromycin (AZM). The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptor, allowing virus entry and replication in host cells. The viral main protease (Mpro) and host cathepsin L (CTSL) are among the proteolytic systems involved in SARS-CoV-2 S protein activation. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. The findings showed AZM affinity scores (ΔG) with strong interactions with ACE2, CTSL, Mpro and RBD. CQ affinity scores showed three low-energy results (less negative) with ACE2, CTSL and RBD, and a firm bond score with Mpro. For HCQ, two results (ACE2 and Mpro) were firmly bound to the receptors, however CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between HCQ and CQ with ACE2 and Mpro were probably due to structural differences between the drugs. On other hand, AZM not only showed more negative (better) values in affinity, but also in the number of interactions in all targets. Nevertheless, further studies are needed to investigate the antiviral properties of these drugs against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Azithromycin/chemistry , Betacoronavirus/chemistry , Cathepsin L/chemistry , Chloroquine/chemistry , Cysteine Endopeptidases/chemistry , Hydroxychloroquine/chemistry , Peptidyl-Dipeptidase A/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Viral Nonstructural Proteins/chemistry , Amino Acid Motifs , Antiviral Agents/chemistry , Azithromycin/pharmacology , Betacoronavirus/metabolism , Binding Sites , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cysteine Endopeptidases/metabolism , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Hydroxychloroquine/pharmacology , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Virus Attachment/drug effects
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.
Chem Commun (Camb) ; 56(62): 8854-8856, 2020 Aug 04.
Article in English | MEDLINE | ID: covidwho-635466

ABSTRACT

Using a combination of enhanced sampling molecular dynamics techniques and non-equilibrium alchemical transformations with full atomistic details, we have shown that hydroxychloroquine (HCQ) may act as a mild inhibitor of important functional proteins for SARS-CoV2 replication, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.


Subject(s)
Cysteine Endopeptidases/metabolism , Hydroxychloroquine/metabolism , Molecular Dynamics Simulation , Papain/metabolism , RNA Replicase/metabolism , Viral Nonstructural Proteins/metabolism , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , Catalytic Domain , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Cysteine Endopeptidases/chemistry , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/therapeutic use , Pandemics , Papain/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , RNA Replicase/chemistry , Viral Nonstructural Proteins/chemistry
4.
Farm Hosp ; 44(7): 49-52, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-603418

ABSTRACT

As in other areas of the health system, COVID-19 has had a dramatic impact on  hospital compounding. This area has faced numerous challenges, including the  shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir  suspension), the use of new preparations for SARS-CoV-2 (tocilizumab,  remdesivir), or requests from overwhelmed wards unable to assume the safe  preparation of a high volume of medications (intravenous solutions). The  demand for all types of preparations (topic and oral medications, intravenous  solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high  demand for preparations. In addition, the pandemic has revealed the scarcity of  research on such basic aspects as agent stability and drug compatibility. One of  the most relevant conclusions drawn from the COVID-19 pandemic is that the  basic areas of hospital pharmacy, along with other, must be maintained and  reinforced, as these are the areas that make us essential.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Drug Compounding , Pandemics , Pharmacy Service, Hospital/organization & administration , Pneumonia, Viral/drug therapy , Administration, Oral , Antiviral Agents/supply & distribution , Antiviral Agents/therapeutic use , Blood Component Transfusion , Disinfection , Drug Administration Routes , Drug Interactions , Drug Stability , Equipment Contamination/prevention & control , Excipients , Forecasting , Home Care Services , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Infusions, Intravenous , Lopinavir/administration & dosage , Personal Protective Equipment/supply & distribution , Platelet-Rich Plasma , Ritonavir/administration & dosage , Solutions
5.
Farm Hosp ; 44(7): 49-52, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-599578

ABSTRACT

As in other areas of the health system, COVID-19 has had a dramatic impact on  hospital compounding. This area has faced numerous challenges, including the  shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir  suspension), the use of new preparations for SARS-CoV-2 (tocilizumab,  remdesivir), or requests from overwhelmed wards unable to assume the safe  preparation of a high volume of medications (intravenous solutions). The  demand for all types of preparations (topic and oral medications, intravenous  solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high  demand for preparations. In addition, the pandemic has revealed the scarcity of  research on such basic aspects as agent stability and drug compatibility. One of  the most relevant conclusions drawn from the COVID-19 pandemic is that the  basic areas of hospital pharmacy, along with other, must be maintained and  reinforced, as these are the areas that make us essential.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Drug Compounding , Pandemics , Pharmacy Service, Hospital/organization & administration , Pneumonia, Viral/drug therapy , Administration, Oral , Antiviral Agents/supply & distribution , Antiviral Agents/therapeutic use , Blood Component Transfusion , Disinfection , Drug Administration Routes , Drug Interactions , Drug Stability , Equipment Contamination/prevention & control , Excipients , Forecasting , Home Care Services , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Infusions, Intravenous , Lopinavir/administration & dosage , Personal Protective Equipment/supply & distribution , Platelet-Rich Plasma , Ritonavir/administration & dosage , Solutions
6.
Farm Hosp ; 44(7): 49-52, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-597485

ABSTRACT

As in other areas of the health system, COVID-19 has had a dramatic impact on  hospital compounding. This area has faced numerous challenges, including the  shortage of frequent-use products (hydroalcoholic solutions, lopinavir/ritonavir  suspension), the use of new preparations for SARS-CoV-2 (tocilizumab,  remdesivir), or requests from overwhelmed wards unable to assume the safe  preparation of a high volume of medications (intravenous solutions). The  demand for all types of preparations (topic and oral medications, intravenous  solutions) has increased dramatically. This increase has highlighted the shortage of resources allocated to this area, which has made it difficult to meet the high  demand for preparations. In addition, the pandemic has revealed the scarcity of  research on such basic aspects as agent stability and drug compatibility. One of  the most relevant conclusions drawn from the COVID-19 pandemic is that the  basic areas of hospital pharmacy, along with other, must be maintained and  reinforced, as these are the areas that make us essential.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Drug Compounding , Pandemics , Pharmacy Service, Hospital/organization & administration , Pneumonia, Viral/drug therapy , Administration, Oral , Antiviral Agents/supply & distribution , Antiviral Agents/therapeutic use , Blood Component Transfusion , Disinfection , Drug Administration Routes , Drug Interactions , Drug Stability , Equipment Contamination/prevention & control , Excipients , Forecasting , Home Care Services , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Infusions, Intravenous , Lopinavir/administration & dosage , Personal Protective Equipment/supply & distribution , Platelet-Rich Plasma , Ritonavir/administration & dosage , Solutions
7.
Int J Antimicrob Agents ; 56(2): 106020, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-378805

ABSTRACT

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.


Subject(s)
Antiviral Agents/pharmacology , Azithromycin/pharmacology , Betacoronavirus/drug effects , G(M1) Ganglioside/chemistry , Hydroxychloroquine/pharmacology , Peptidyl-Dipeptidase A/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Antiviral Agents/chemistry , Azithromycin/chemistry , Betacoronavirus/growth & development , Betacoronavirus/metabolism , Binding Sites , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Synergism , G(M1) Ganglioside/antagonists & inhibitors , G(M1) Ganglioside/metabolism , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/chemistry , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Sequence Alignment , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Virus Attachment/drug effects
8.
Molecules ; 25(8)2020 Apr 16.
Article in English | MEDLINE | ID: covidwho-110604

ABSTRACT

The desperate need to find drugs for COVID-19 has indicated repurposing strategies as our quickest way to obtain efficacious medicines. One of the options under investigation is the old antimalarial drug, chloroquine, and its analog, hydroxychloroquine. Developed as synthetic succedanea of cinchona alkaloids, these chiral antimalarials are currently in use as the racemate. Besides the ethical concern related to accelerated large-scale clinical trials of drugs with unproven efficacy, the known potential detrimental cardiac effects of these drugs should also be considered. In principle, the safety profile might be ameliorated by using chloroquine/hydroxychloroquine single enantiomers in place of the racemate.


Subject(s)
Betacoronavirus , Chloroquine/adverse effects , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Antimalarials , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Arrhythmias, Cardiac/chemically induced , Cardiotoxicity , Chloroquine/chemistry , Chloroquine/pharmacology , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/chemistry , Hydroxychloroquine/therapeutic use , Pandemics , Stereoisomerism
9.
Drug Discov Today ; 25(6): 956-958, 2020 06.
Article in English | MEDLINE | ID: covidwho-88528

ABSTRACT

This article examines three aspects of antivirals, such as hydroxychloroquine, chloroquine, and remdesvir, as they might relate to the treatment of a viral infection such as COVID-19: (i) the use of vaporization for the delivery of antivirals, with the bulk constituents having mild antiviral efficacy; (ii) the application of a marine natural product extract as opposed to a single molecule as an antiviral agent; and (iii) a counter intuitive approach to formulation that is, in part, based on delivering multiple species that fall into three categories: building blocks for the virus to accelerate replication; an energy source for the infected cell to boost its immune response; and the species that antagonize or provide toxicity to the virus.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Aquatic Organisms/chemistry , Biological Products/administration & dosage , Biological Products/chemistry , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/chemistry , Chloroquine/administration & dosage , Chloroquine/chemistry , Coronavirus Infections/drug therapy , Drug Compounding , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/chemistry , Models, Molecular , Pandemics , Pneumonia, Viral/drug therapy , Volatilization
10.
Int J Antimicrob Agents ; 55(5): 105960, 2020 May.
Article in English | MEDLINE | ID: covidwho-65372

ABSTRACT

The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.


Subject(s)
Betacoronavirus/drug effects , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Hydroxychloroquine/pharmacology , Pneumonia, Viral/drug therapy , Amino Acid Sequence , Betacoronavirus/chemistry , Chloroquine/chemistry , Chloroquine/therapeutic use , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/therapeutic use , Models, Molecular , Molecular Targeted Therapy , Pandemics , Protein Structure, Quaternary , Protein Structure, Tertiary , Sequence Analysis, Protein , Spike Glycoprotein, Coronavirus/chemistry
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