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1.
Mycoses ; 65(4): 458-465, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1691477

ABSTRACT

BACKGROUND: COVID-19-associated invasive pulmonary aspergillosis (CAPA) is associated with increased mortality. Cases of CAPA caused by azole-resistant Aspergillus fumigatus strains have been reported. OBJECTIVES: To analyse the twelve-month CAPA prevalence in a German tertiary care hospital and to characterise clinical A. fumigatus isolates from two German hospitals by antifungal susceptibility testing and microsatellite genotyping. PATIENTS/METHODS: Retrospective observational study in critically ill adults from intensive care units with COVID-19 from 17 February 2020 until 16 February 2021 and collection of A. fumigatus isolates from two German centres. EUCAST broth microdilution for four azole compounds and microsatellite PCR with nine markers were performed for each collected isolate (N = 27) and additional for three non-COVID A. fumigatus isolates. RESULTS: welve-month CAPA prevalence was 7.2% (30/414), and the rate of azole-resistant A. fumigatus isolates from patients with CAPA was 3.7% with detection of one TR34/L98H mutation. The microsatellite analysis revealed no major clustering of the isolates. Sequential isolates mainly showed the same genotype over time. CONCLUSIONS: Our findings demonstrate similar CAPA prevalence to other reports and a low azole-resistance rate. Genotyping of A. fumigatus showed polyclonal distribution except for sequential isolates.


Subject(s)
COVID-19 , Pulmonary Aspergillosis , Adult , Antifungal Agents/pharmacology , Aspergillus fumigatus , Azoles/pharmacology , Drug Resistance, Fungal/genetics , Fungal Proteins/genetics , Humans , Intensive Care Units , Microbial Sensitivity Tests , Pulmonary Aspergillosis/complications , Pulmonary Aspergillosis/epidemiology
2.
Nat Commun ; 12(1): 3061, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1387342

ABSTRACT

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.


Subject(s)
Azoles/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Organoselenium Compounds/pharmacology , SARS-CoV-2/enzymology , Antiviral Agents/pharmacology , Azoles/chemistry , Catalytic Domain , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine/chemistry , Hydrolysis , Isoindoles , Models, Molecular , Organoselenium Compounds/chemistry , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Reference Standards , SARS-CoV-2/drug effects , Salicylanilides/chemistry , Salicylanilides/pharmacology , Selenium/metabolism
3.
Mol Inform ; 40(8): e2100028, 2021 08.
Article in English | MEDLINE | ID: covidwho-1345038

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 has mobilized scientific attention in search of a treatment. The cysteine-proteases, main protease (Mpro) and papain-like protease (PLpro) are important targets for antiviral drugs. In this work, we simulate the interactions between the Mpro and PLpro with Ebselen, its metabolites and derivatives with the aim of finding molecules that can potentially inhibit these enzymes. The docking data demonstrate that there are two main interactions between the thiol (-SH) group of Cys (from the protease active sites) and the electrophilic centers of the organoselenium molecules, i. e. the interaction with the carbonyl group (O=C… SH) and the interaction with the Se moiety (Se… SH). Both interactions may lead to an adduct formation and enzyme inhibition. Density Functional Theory (DFT) calculations with Ebselen indicate that the energetics of the thiol nucleophilic attack is more favorable on Se than on the carbonyl group, which is in accordance with experimental data (Jin et al. Nature, 2020, 582, 289-293). Therefore, organoselenium molecules should be further explored as inhibitors of the SARS-CoV-2 proteases. Furthermore, we suggest that some metabolites of Ebselen (e. g. Ebselen diselenide and methylebselenoxide) and derivatives ethaselen and ebsulfur should be tested in vitro as inhibitors of virus replication and its proteases.


Subject(s)
Azoles/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases/metabolism , Organoselenium Compounds/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Viral Matrix Proteins/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Azoles/chemistry , Azoles/metabolism , COVID-19/metabolism , Catalytic Domain/drug effects , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Drug Discovery , Humans , Isoindoles , Molecular Docking Simulation , Organoselenium Compounds/chemistry , Organoselenium Compounds/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Viral Matrix Proteins/antagonists & inhibitors
4.
Molecules ; 26(14)2021 Jul 12.
Article in English | MEDLINE | ID: covidwho-1323315

ABSTRACT

Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.


Subject(s)
Azoles/chemistry , Azoles/chemical synthesis , Azoles/pharmacology , Organoselenium Compounds/chemistry , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/pharmacology , Animals , Anti-Infective Agents/pharmacology , Antioxidants/pharmacology , Antiviral Agents/pharmacology , Biomimetics/methods , Cyclooxygenase Inhibitors/pharmacology , Glutathione Peroxidase/metabolism , Glutathione Peroxidase/pharmacology , Humans , Isoindoles , Molecular Structure , Neuroprotective Agents/pharmacology , Selenium/chemistry , Selenoproteins/chemical synthesis , Selenoproteins/pharmacology
5.
Biochem J ; 478(13): 2499-2515, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1291175

ABSTRACT

The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Evaluation, Preclinical , SARS-CoV-2/enzymology , Small Molecule Libraries/pharmacology , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Azoles/pharmacology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Enzyme Assays , Fluorescence Resonance Energy Transfer , High-Throughput Screening Assays , Isoindoles , Leupeptins/pharmacology , Organoselenium Compounds/pharmacology , Peptidomimetics , RNA-Binding Proteins/metabolism , Reproducibility of Results , SARS-CoV-2/drug effects , Small Molecule Libraries/chemistry , Vero Cells , Viral Nonstructural Proteins/metabolism
6.
Int J Mol Sci ; 22(9)2021 Apr 25.
Article in English | MEDLINE | ID: covidwho-1231493

ABSTRACT

Candida auris is a novel and major fungal pathogen that has triggered several outbreaks in the last decade. The few drugs available to treat fungal diseases, the fact that this yeast has a high rate of multidrug resistance and the occurrence of misleading identifications, and the ability of forming biofilms (naturally more resistant to drugs) has made treatments of C. auris infections highly difficult. This review intends to quickly illustrate the main issues in C. auris identification, available treatments and the associated mechanisms of resistance, and the novel and alternative treatment and drugs (natural and synthetic) that have been recently reported.


Subject(s)
Antifungal Agents/pharmacology , Candida/isolation & purification , Candidiasis/drug therapy , Drug Resistance, Fungal/drug effects , Antifungal Agents/chemistry , Antifungal Agents/therapeutic use , Azoles/pharmacology , Candida/drug effects , Candidiasis/microbiology , Drug Therapy, Combination , Echinocandins/pharmacology , Humans , Mycology/methods , Polyenes/pharmacology , Treatment Failure
7.
Sci Rep ; 11(1): 3640, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1078609

ABSTRACT

An efficient treatment against a COVID-19 disease, caused by the novel coronavirus SARS-CoV-2 (CoV2), remains a challenge. The papain-like protease (PLpro) from the human coronavirus is a protease that plays a critical role in virus replication. Moreover, CoV2 uses this enzyme to modulate the host's immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. We used Approximate Bayesian Computation tools, molecular modelling and enzyme activity studies to identify highly active inhibitors of the PLpro. We discovered organoselenium compounds, ebselen and its structural analogues, as a novel approach for inhibiting the activity of PLproCoV2. Furthermore, we identified, for the first time, inhibitors of PLproCoV2 showing potency in the nanomolar range. Moreover, we found a difference between PLpro from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression.


Subject(s)
Antiviral Agents/pharmacology , Azoles/pharmacology , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Molecular Docking Simulation , Organoselenium Compounds/pharmacology , Protease Inhibitors/pharmacology , Antiviral Agents/chemistry , Azoles/chemistry , Binding Sites , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Isoindoles , Organoselenium Compounds/chemistry , Protease Inhibitors/chemistry , Protein Binding
8.
Lancet Infect Dis ; 21(6): e149-e162, 2021 06.
Article in English | MEDLINE | ID: covidwho-974782

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.


Subject(s)
Antifungal Agents/therapeutic use , COVID-19/complications , Coinfection/drug therapy , Pulmonary Aspergillosis/complications , Pulmonary Aspergillosis/drug therapy , Amphotericin B , Azoles/pharmacology , Humans , Nitriles , Pyridines , SARS-CoV-2 , Triazoles , Voriconazole/therapeutic use
9.
Nature ; 581(7808): 252-255, 2020 05.
Article in English | MEDLINE | ID: covidwho-831180

Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/immunology , Drug Design , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Vaccines , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/chemistry , Azoles/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , COVID-19 Vaccines , China , Coronavirus 3C Proteases , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Coronavirus Papain-Like Proteases , Coronavirus RNA-Dependent RNA Polymerase , Cryoelectron Microscopy , Crystallization , Crystallography, X-Ray , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Evaluation, Preclinical , Germany , High-Throughput Screening Assays , Humans , Isoindoles , Mice , National Institutes of Health (U.S.)/economics , National Institutes of Health (U.S.)/organization & administration , Organoselenium Compounds/pharmacology , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Protease Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Synchrotrons , Time Factors , United Kingdom , United States , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Proteins/immunology
10.
Sci Adv ; 6(37)2020 09.
Article in English | MEDLINE | ID: covidwho-760208

ABSTRACT

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus' main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Azoles/metabolism , Azoles/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/metabolism , Organoselenium Compounds/metabolism , Organoselenium Compounds/pharmacology , Pneumonia, Viral/drug therapy , Viral Nonstructural Proteins/metabolism , Antiviral Agents/metabolism , Betacoronavirus/metabolism , Binding Sites , COVID-19 , Catalytic Domain/drug effects , Coronavirus 3C Proteases , Drug Repositioning , Humans , Isoindoles , Models, Molecular , Molecular Dynamics Simulation , Pandemics , Protein Conformation/drug effects , SARS-CoV-2
11.
Redox Biol ; 37: 101715, 2020 10.
Article in English | MEDLINE | ID: covidwho-752931

ABSTRACT

Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Selenium/immunology , Selenoproteins/immunology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Azoles/pharmacology , Azoles/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/immunology , Cytokines/immunology , Humans , Inflammation/drug therapy , Isoindoles , Organoselenium Compounds/pharmacology , Organoselenium Compounds/therapeutic use , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Viral Protease Inhibitors/pharmacology , Viral Protease Inhibitors/therapeutic use
12.
Comput Biol Chem ; 89: 107372, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-743928

ABSTRACT

The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus Protease Inhibitors/pharmacology , Protein Multimerization/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Small Molecule Libraries/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Azoles/chemical synthesis , Azoles/chemistry , Azoles/pharmacology , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemical synthesis , Coronavirus Protease Inhibitors/chemistry , Humans , Isoindoles , Ligands , Lopinavir/chemical synthesis , Lopinavir/chemistry , Lopinavir/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Ritonavir/chemical synthesis , Ritonavir/chemistry , Ritonavir/pharmacology , SARS-CoV-2/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry
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