Hydrogen sulfide (H2S) is an endogenous gasotransmitter with cardioprotective and antiviral effects. In this work, new cysteine-selective nucleoside-H2S-donor hybrid molecules were prepared by conjugating nucleoside biomolecules with a thiol-activatable dithioacetyl group. 5'-Dithioacetate derivatives were synthesized from the canonical nucleosides (uridine, adenosine, cytidine, guanosine and thymidine), and the putative 5'-thio metabolites were also produced from uridine and adenosine. According to our measurements made with an H2S-specific sensor, nucleoside dithioacetates are moderately fast H2S donors, the guanosine derivative showed the fastest kinetics and the adenosine derivative the slowest. The antioxidant activity of 5'-thionucleosides is significantly higher than that of trolox, but lower than that of ascorbic acid, while intact dithioacetates have no remarkable antioxidant effect. In human Calu cells, the guanosine derivative showed a moderate anti-SARS-CoV-2 effect which was also confirmed by virus yield reduction assay. Dithioacetyl-adenosine and its metabolite showed similar acute cardiac effects as adenosine, however, it is noteworthy that both 5'-thio modified adenosines increased left ventricular ejection fraction or stroke volume, which was not observed with native adenosine.
- Klíčová slova
- Antioxidant, Antiviral, Dithioacetate, H2S donor, H2S release kinetics, Nucleoside, SARS-CoV-2,
- MeSH
- adenosin analogy a deriváty MeSH
- antioxidancia * farmakologie chemie MeSH
- antivirové látky * farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- farmakoterapie COVID-19 MeSH
- lidé MeSH
- nukleosidy farmakologie chemie metabolismus MeSH
- SARS-CoV-2 účinky léků metabolismus MeSH
- sulfan * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adenosin MeSH
- antioxidancia * MeSH
- antivirové látky * MeSH
- nukleosidy MeSH
- sulfan * MeSH
Enveloped viruses, such as flaviviruses and coronaviruses, are pathogens of significant medical concern that cause severe infections in humans. Some photosensitizers are known to possess virucidal activity against enveloped viruses, targeting their lipid bilayer. Here we report a series of halogenated difluoroboron-dipyrromethene (BODIPYs) photosensitizers with strong virus-inactivating activity. Our structure-activity relationship analysis revealed that BODIPY scaffolds with a heavy halogen atom demonstrate significant efficacy against both tick-borne encephalitis virus (TBEV; Flaviviridae family) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae family) along with high singlet oxygen quantum yields. Moreover, select compounds also inactivated other enveloped viruses, such as herpes simplex virus type 1 and monkeypox virus. The nature and length of the alkyl side chain notably influenced the virus-inactivating activity of BODIPY molecules. Furthermore, molecular dynamics studies highlighted the critical importance of the positioning of the chromophore moiety within the lipid bilayer. As membrane-targeting photosensitizers, BODIPYs interact directly with virus particles, causing damage to the viral envelope membranes. Thus, TBEV pretreated with BODIPY was completely noninfective for lab mice. Consequently, BODIPY-based photosensitizers hold potential either as broad-spectrum virus-inactivating antivirals against a variety of phylogenetically unrelated enveloped viruses or as potent inactivators of viruses for the development of vaccines for preventing life-threatening emerging viral diseases.
- Klíčová slova
- BODIPY, enveloped viruses, membrane-targeting photosensitizer, singlet oxygen photogeneration, virus-inactivating activity,
- MeSH
- antivirové látky * farmakologie chemie MeSH
- Cercopithecus aethiops MeSH
- fotosenzibilizující látky * chemie farmakologie účinky záření MeSH
- halogenace MeSH
- lidé MeSH
- myši MeSH
- porfobilinogen analogy a deriváty chemie farmakologie MeSH
- SARS-CoV-2 účinky léků MeSH
- singletový kyslík * metabolismus chemie MeSH
- sloučeniny boru * chemie farmakologie MeSH
- Vero buňky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene MeSH Prohlížeč
- antivirové látky * MeSH
- dipyrromethene MeSH Prohlížeč
- fotosenzibilizující látky * MeSH
- porfobilinogen MeSH
- singletový kyslík * MeSH
- sloučeniny boru * MeSH
Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MICMtb H37Ra = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future.
- Klíčová slova
- antibacterial, antimycobacterial, antiproliferative, drug design, pyridine, tuberculosis,
- MeSH
- acetamidy * chemie farmakologie MeSH
- antifungální látky farmakologie chemie chemická syntéza MeSH
- antituberkulotika farmakologie chemie MeSH
- antitumorózní látky farmakologie chemie MeSH
- buňky Hep G2 MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Mycobacterium tuberculosis * účinky léků MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- pyridiny chemie farmakologie MeSH
- SARS-CoV-2 účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetamidy * MeSH
- antifungální látky MeSH
- antituberkulotika MeSH
- antitumorózní látky MeSH
- pyridiny MeSH
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor Mpro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the WT glutamine at the P1 position with isoleucine retains Mpro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter assay suitable for compound library screening and evaluation in HEK293T cells. This assay can detect both overall Mpro inhibition and the fraction of uncleaved precursor form of Mpro through separable fluorescent signals. We observed that inhibitory compounds preferentially block mature Mpro. Bofutrelvir and a novel compound designed in-house showed the lowest selectivity between precursor and mature Mpro, indicating that inhibition of both forms may be possible. Additionally, we observed positive modulation of precursor activity at low concentrations of inhibitors. Our findings help expand understanding of the SARS-CoV-2 viral life cycle and may facilitate development of strategies to target precursor form of Mpro for inhibition or premature activation of Mpro.
- Klíčová slova
- Förster resonance energy transfer (FRET), SARS-CoV-2 main protease, activation, autoprocessing, cell-based assay, fluorescence cross-correlation spectroscopy (FCCS), fluorescence life-time imaging, inhibitor, maturation, nsp5, precursor, protease, virus,
- MeSH
- antivirové látky * farmakologie chemie MeSH
- farmakoterapie COVID-19 MeSH
- HEK293 buňky MeSH
- inhibitory proteas farmakologie chemie MeSH
- koronavirové proteasy 3C * metabolismus antagonisté a inhibitory chemie genetika MeSH
- lidé MeSH
- mutace MeSH
- objevování léků * metody MeSH
- proteolýza MeSH
- SARS-CoV-2 * enzymologie účinky léků metabolismus genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 3C-like proteinase, SARS-CoV-2 MeSH Prohlížeč
- antivirové látky * MeSH
- inhibitory proteas MeSH
- koronavirové proteasy 3C * MeSH
This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ9-tetrahydrocannabinol (Δ9-THC) Cannabis sativa L. genotypes. Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes. The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC50 < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid. On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract's pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.
- Klíčová slova
- Cannabis sativa, SARS‐CoV‐2, antiviral activity, chemical composition, phytocannabinoids,
- MeSH
- antivirové látky * farmakologie chemie MeSH
- Cannabis * chemie MeSH
- ethanol chemie MeSH
- farmakoterapie COVID-19 MeSH
- fytonutrienty farmakologie chemie izolace a purifikace MeSH
- genotyp * MeSH
- kanabinoidy farmakologie chemie MeSH
- lidé MeSH
- rostlinné extrakty * farmakologie chemie MeSH
- SARS-CoV-2 * účinky léků genetika MeSH
- sekundární metabolismus MeSH
- tandemová hmotnostní spektrometrie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky * MeSH
- ethanol MeSH
- fytonutrienty MeSH
- kanabinoidy MeSH
- rostlinné extrakty * MeSH
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.
- Klíčová slova
- SARS-CoV-2, in vitro assays, spike glycoprotein, virtual screening,
- MeSH
- angiotensin konvertující enzym 2 * metabolismus chemie MeSH
- antivirové látky farmakologie chemie metabolismus MeSH
- COVID-19 virologie metabolismus MeSH
- farmakoterapie COVID-19 MeSH
- glykoprotein S, koronavirus * metabolismus chemie MeSH
- kyselina linolová metabolismus chemie MeSH
- lidé MeSH
- proteiny vázající mastné kyseliny metabolismus MeSH
- SARS-CoV-2 * metabolismus účinky léků MeSH
- simulace molekulového dockingu * MeSH
- vazba proteinů * MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ACE2 protein, human MeSH Prohlížeč
- angiotensin konvertující enzym 2 * MeSH
- antivirové látky MeSH
- glykoprotein S, koronavirus * MeSH
- kyselina linolová MeSH
- proteiny vázající mastné kyseliny MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
The use of Fpocket and virtual screening techniques enabled us to identify potential allosteric druggable pockets within the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Of the compounds screened, compound 1 was identified as a promising inhibitor, lowering a SARS-CoV-2 RdRp activity to 57 % in an enzymatic assay at 10 μM concentration. The structure of compound 1 was subsequently optimized in order to preserve or enhance inhibitory activity. This involved the substitution of problematic ester and aromatic nitro groups with more inert functionalities. The N,N'-diphenylurea scaffold with two NH groups was identified as essential for the compound's activity but also exhibited high toxicity in Calu-3 cells. To address this issue, a scaffold hopping approach was employed to replace the urea core with potentially less toxic urea isosteres. This approach yielded several structural analogues with notable activity, specifically 2,2'-bisimidazol (in compound 55 with residual activity RA=42 %) and (1H-imidazol-2-yl)urea (in compounds 59 and 60, with RA=50 and 28 %, respectively). Despite these advances, toxicity remained a major concern. These compounds represent a promising starting point for further structure-activity relationship studies of allosteric inhibitors of SARS-CoV-2 RdRp, with the goal of reducing their cytotoxicity and improving aqueous solubility.
- Klíčová slova
- RdRp; remdesivir, SAR study, SARS-CoV-2, allosteric inhibitor, scaffold hopping,
- MeSH
- alosterická regulace účinky léků MeSH
- antivirové látky * farmakologie chemie chemická syntéza MeSH
- inhibitory enzymů farmakologie chemie chemická syntéza MeSH
- koronavirová RNA-replikasa antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- RNA-dependentní RNA-polymerasa antagonisté a inhibitory metabolismus MeSH
- SARS-CoV-2 * účinky léků enzymologie MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky * MeSH
- inhibitory enzymů MeSH
- koronavirová RNA-replikasa MeSH
- RNA-dependentní RNA-polymerasa MeSH
BACKGROUND: This research article delves into the battle against the COVID-19 pandemic, focusing on the efficacy and, particularly, the safety of the combination of nirmatrelvir with ritonavir, which is found in the pharmaceutical product Paxlovid®. This study aims to analyze the potential interactions of commonly prescribed medicinal products with Paxlovid®, shedding light on its utilization in specific medical fields. METHODS: Prescription data from the Czech Republic's Institute of Health Information and Statistics (IHIS CR) was analyzed, covering 4 million COVID-19 patients and 87.5 million medication records from September 2019 to February 2022. This study focused on potential drug interactions with Paxlovid among the 50 most frequently prescribed medications, with particular attention to four specialties: general medicine, internal medicine, infectious diseases, and diabetology. RESULTS: In this study of the 50 most commonly prescribed drugs, 56% showed no interaction with Paxlovid, 30% had a potential for interaction, and 14% were not specifically mentioned in relation to Paxlovid, with no drugs found to be contraindicated overall. However, in specific medical fields, including diabetology, infectious diseases, internal medicine, and general medicine, certain drugs had potential interactions when co-administered with Paxlovid. CONCLUSIONS: Paxlovid remains a valuable option for early COVID-19 treatment but requires a careful consideration of potential drug interactions, especially in high-risk specialties. A thorough assessment of concurrent medications is essential to optimize safety and efficacy in patients receiving Paxlovid.
- Klíčová slova
- COVID-19, Paxlovid, drug interactions, nirmatrelvir, ritonavir,
- MeSH
- antivirové látky škodlivé účinky terapeutické užití MeSH
- COVID-19 epidemiologie MeSH
- farmakoterapie COVID-19 * MeSH
- fixní kombinace léků * MeSH
- lékové interakce * MeSH
- lidé MeSH
- ritonavir * terapeutické užití škodlivé účinky MeSH
- SARS-CoV-2 účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- antivirové látky MeSH
- fixní kombinace léků * MeSH
- ritonavir * MeSH
INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.
- Klíčová slova
- ACE2, cytokine storm, ectoine, nasal epithelium, polyhydroxylated fullerene, spike,
- MeSH
- aminokyseliny diaminové MeSH
- angiotensin konvertující enzym 2 metabolismus MeSH
- COVID-19 * prevence a kontrola MeSH
- cytokiny metabolismus MeSH
- epitelové buňky * účinky léků virologie MeSH
- fullereny * farmakologie chemie MeSH
- glykoprotein S, koronavirus * metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- nanočástice * chemie MeSH
- nosní sliznice účinky léků cytologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- SARS-CoV-2 * účinky léků MeSH
- syndrom uvolnění cytokinů * prevence a kontrola MeSH
- viabilita buněk * účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminokyseliny diaminové MeSH
- angiotensin konvertující enzym 2 MeSH
- cytokiny MeSH
- ectoine MeSH Prohlížeč
- fullerenol MeSH Prohlížeč
- fullereny * MeSH
- glykoprotein S, koronavirus * MeSH
- reaktivní formy kyslíku MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
Ultraviolet-C (UV-C) radiation and ozone gas are potential mechanisms employed to inactivate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), each exhibiting distinct molecular-level modalities of action. To elucidate these disparities and deepen our understanding, we delve into the intricacies of SARS-CoV-2 inactivation via UV-C and ozone gas treatments, exploring their distinct molecular-level impacts utilizing a suite of advanced techniques, including biological atomic force microscopy (Bio-AFM) and single virus force spectroscopy (SVFS). Whereas UV-C exhibited no perceivable alterations in virus size or surface topography, ozone gas treatment elucidated pronounced changes in both parameters, intensifying with prolonged exposure. Furthermore, a nuanced difference was observed in virus-host cell binding post-treatment: ozone gas distinctly reduced SARS-CoV-2 binding to host cells, while UV-C maintained the status quo. The results derived from these methodical explorations underscore the pivotal role of advanced Bio-AFM techniques and SVFS in enhancing our understanding of virus inactivation mechanisms, offering invaluable insights for future research and applications in viral contamination mitigation.
- Klíčová slova
- binding activity, infectivity test, sterilization mechanisms, structural characteristics, topographical characteristics,
- MeSH
- Cercopithecus aethiops MeSH
- COVID-19 * MeSH
- inaktivace viru * účinky léků účinky záření MeSH
- lidé MeSH
- mikroskopie atomárních sil * MeSH
- ozon * chemie farmakologie MeSH
- plazmové plyny chemie farmakologie MeSH
- SARS-CoV-2 * účinky léků MeSH
- sterilizace metody MeSH
- ultrafialové záření * MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ozon * MeSH
- plazmové plyny MeSH
