The Trimeric Artesunate Analog TF27, a Broadly Acting Anti-Infective Model Drug, Exerts Pronounced Anti-SARS-CoV-2 Activity Spanning Variants and Host Cell Types DOI Creative Commons
Friedrich Hahn,

Christina Wangen,

Sigrun Häge

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 15(1), P. 115 - 115

Published: Dec. 29, 2022

Starting in 2019, the spread of respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated pandemic corona virus disease (COVID-19) has led to enormous efforts development medical countermeasures. Although innovative vaccines have scaled back number severe COVID cases, emergence omicron variant (B.1.1.529) illustrates how vaccine struggles keep pace with viral evolution. On other hand, while recently approved antiviral drugs remdesivir, molnupiravir, Paxlovid are considered as broadly acting anti-coronavirus therapeutics, only molnupiravir orally available none these recommended for prophylactic use. Thus, so far unexploited small molecules, targeting strategies, mechanisms urgently needed address issues current putative future outbreaks newly emerging variants concern. Recently, we others described anti-infective potential particularly pronounced activity artesunate related compounds trioxane/sesquiterpene class. In particular, trimeric derivative TF27 demonstrated strong anti-cytomegalovirus at nanomolar concentrations vitro well vivo efficacy after oral administration therapeutic even treatment settings. Here, extended this analysis by evaluating its anti-SARS-CoV-2 potential. Our main findings follows: (i) compound exerted (EC50 = 0.46 ± 0.20 µM), (ii) was clearly distinct from induction cytotoxicity, (iii) pretreatment prevented replication cultured cells, (iv) likewise been Calu-3 human lung Caco-2 colon cells infected wild-type, delta, or SARS-CoV-2, respectively, (v) combination treatments revealed synergistic interaction GC376, but antagonistic EIDD-1931. Combined, data thus highlight trioxane further pharmacologic towards improved options COVID-specific medication.

Language: Английский

A Monoclonal Human Alveolar Epithelial Cell Line (“Arlo”) with Pronounced Barrier Function for Studying Drug Permeability and Viral Infections DOI Creative Commons
Patrick Carius, Annemarie Jungmann,

Marco Bechtel

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(8)

Published: Feb. 7, 2023

Abstract In the development of orally inhaled drug products preclinical animal models regularly fail to predict pharmacological as well toxicological responses in humans. Models based on human cells and tissues are potential alternatives experimentation allowing for isolation essential processes biology making them accessible vitro. Here, generation a novel monoclonal cell line “Arlo,” derived from polyclonal alveolar epithelium lentivirus immortalized hAELVi via single‐cell printing, its characterization model building block future complex vitro is described. “Arlo” systematically compared primary epithelial (hAEpCs) line. show enhanced barrier properties with high transepithelial electrical resistance (TEER) ≈3000 Ω cm 2 difference (PD) ≈30 mV under air–liquid interface (ALI) conditions, that can be modulated. The grow polarized monolayer express genes relevant integrity homeostasis observed hAEpCs. Successful productive infection severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) proof‐of‐principle study offers an additional, attractive application beyond biopharmaceutical experimentation.

Language: Английский

Citations

13
Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2 DOI Creative Commons
María Gil‐Moles, Cillian O’Beirne, Igor V. Esarev

et al.

RSC Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 14(7), P. 1260 - 1271

Published: Jan. 1, 2023

The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite promising results, metal complexes have been relatively unexplored as agents in general and particular against SARS-CoV-2. Here we report on silver NHC with chloride or iodide counter ligands that are potent inhibitors of the papain-like protease (PLpro) but inactive 3C-like (3CLpro) another protease. Mechanistic studies selected complex confirmed zinc removal from binding domain PLpro relevant factor their activity. In addition, enzyme kinetic experiments revealed is an uncompetitive inhibitor this rare type inhibition it offers great pharmacological advantages terms selectivity. showed very low absent host cell toxicity triggered strong effects viral replication cells infected SARS-CoV-2, making them future

Language: Английский

Citations

13
Omicron‐induced interferon signaling prevents influenza A H1N1 and H5N1 virus infection DOI Creative Commons
Denisa Bojková,

Marco Bechtel,

Tamara Rothenburger

et al.

Journal of Medical Virology, Journal Year: 2023, Volume and Issue: 95(3)

Published: March 1, 2023

Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show and BA.5 but not Delta induce an antiviral state air-liquid interface cultures of primary human bronchial epithelial cells monocytes. Both subvariants caused the production biologically active types I (α/β) III (λ) interferons protected from super-infection with influenza A viruses. Notably, abortive infection monocytes was sufficient to protect virus infection. Interestingly, while influenza-like illnesses surged during wave England, their spread rapidly declined upon emergence Omicron. Mechanistically, Omicron-induced signaling mediated via double-stranded RNA recognition by MDA5, as MDA5 knockout prevented it. The JAK/STAT inhibitor baricitinib inhibited Omicron-mediated response, suggesting it is MDA5-mediated production, which activates receptors then trigger signaling. In conclusion, our study (1) demonstrates only substantial physiologically relevant models, (2) shows protects super-infection, (3) indicates comparable states.

Language: Английский

Citations

11
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism DOI Open Access
Wesley H. Godfrey,

Kaho Cho,

Xiaojing Deng

et al.

Published: Jan. 30, 2025

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the role glycolytic enzymes in Tregs identified phosphoglycerate mutase (PGAM) as being differentially overexpressed associated with highly phenotype. Pharmacologic or genetic inhibition PGAM reduced Treg function while reciprocally inducing markers pro-inflammatory, helper 17 (Th17)-like state. was dependent contribution 3-phosphoglycerate (3PG), substrate, to de novo serine synthesis. Blocking synthesis from 3PG reversed effect polarization, exogenous directly inhibited polarization. Additionally, altering levels vivo serine/glycine-free diet increased peripheral attenuated autoimmunity murine model multiple sclerosis. Mechanistically, found that limits polarization contributing one-carbon metabolism methylation Treg-associated genes. Inhibiting both vitro autoimmune colitis. Our study identifies novel physiologic highlights interconnectivity between glycolysis, synthesis, metabolism, epigenetic regulation function.

Language: Английский

Citations

0
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism DOI Open Access
Wesley H. Godfrey,

Kaho Cho,

Xiaojing Deng

et al.

Published: Jan. 30, 2025

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the role glycolytic enzymes in Tregs identified phosphoglycerate mutase (PGAM) as being differentially overexpressed associated with highly phenotype. Pharmacologic or genetic inhibition PGAM reduced Treg function while reciprocally inducing markers pro-inflammatory, helper 17 (Th17)-like state. was dependent contribution 3-phosphoglycerate (3PG), substrate, to de novo serine synthesis. Blocking synthesis from 3PG reversed effect polarization, exogenous directly inhibited polarization. Additionally, altering levels vivo serine/glycine-free diet increased peripheral attenuated autoimmunity murine model multiple sclerosis. Mechanistically, found that limits polarization contributing one-carbon metabolism methylation Treg-associated genes. Inhibiting both vitro autoimmune colitis. Our study identifies novel physiologic highlights interconnectivity between glycolysis, synthesis, metabolism, epigenetic regulation function.

Language: Английский

Citations

0
Discovery of anti-SARS-CoV-2 secondary metabolites from the heartwood of Pterocarpus santalinus using multi-informative molecular networking DOI Creative Commons
Andreas Wasilewicz, Julia Zwirchmayr, Benjamin Kirchweger

et al.

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: June 6, 2023

A pigment-depleted extract from the heartwood of Pterocarpus santalinus L. f. (PS-DE) showed promising anti-SARS-CoV-2 activity with an IC50 29.9 μg/mL in Caco-2-F03 cells. To determine potential active constituents within prior to isolation, multi-informative molecular network (MN) was applied. Therefore, separated by high-performance counter-current chromatography (HPCCC) into 11 fractions which were subsequently tested for and analysed UPLC-tandem mass spectrometry (MS2). The resulting MN combines bioactivity data MS2 data. analysis led targeted isolation seven compounds including one pterocarpan (7) reported first time as constituent P. four so far undescribed natural products (NPs) that belong compound classes arylpropanes (9), isoflavanones (10) coumestans (16) 3-arylcoumarins (17), respectively. In total, 15 synthetic isoflavonoid is structurally related metabolites activity. Thereby, two pterocarpans (-)-homopterocarpin (5) (-)-medicarpin (2), stilbene (E)-pterostilbene (1) 7-O-methylgenistein (11) a distinct antiviral values 17.2, 33.4, 34.7, 37.9 µM, respectively, no cytotoxic effects against cells (CC50 > 100 µM). addition, structure-activity relationship (SAR) proposed indicating structural requirements herein presented results support implementation networks powerful tool dereplication bioactive NPs.

Language: Английский

Citations

5
Molecular networking unveils anti-SARS-CoV-2 constituents from traditionally used remedies DOI
Andreas Wasilewicz, Denisa Bojková, Mehdi A. Beniddir

et al.

Journal of Ethnopharmacology, Journal Year: 2023, Volume and Issue: 319, P. 117206 - 117206

Published: Sept. 30, 2023

Language: Английский

Citations

5
Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels DOI

Christina Wangen,

Andrea Raithel,

Julia Tillmanns

et al.

Antiviral Research, Journal Year: 2023, Volume and Issue: 221, P. 105769 - 105769

Published: Dec. 4, 2023

Language: Английский

Citations

5
Synergism of interferon-beta with antiviral drugs against SARS-CoV-2 variants DOI
Denisa Bojková, Richard S. Stack, Tamara Rothenburger

et al.

Journal of Infection, Journal Year: 2022, Volume and Issue: 85(5), P. 573 - 607

Published: July 31, 2022

Language: Английский

Citations

7
The cell cultures in virology: from the past to the future DOI Creative Commons
Т. А. Кузнецова, Н. Н. Беседнова, M. R. Aliev

et al.

Journal of microbiology epidemiology immunobiology, Journal Year: 2024, Volume and Issue: 101(1), P. 143 - 153

Published: March 9, 2024

The aim of the review is to give a brief characteristic cell cultures obtained from mammalian tissues and consider current possibilities prospects for their use in virology. analysis literature data presented main databases, such as Web Science, PubMed, Scopus, Elsevier, Google Scholar RSCI (as July 2023), indicates that various types are currently used virological studies. culture has number advantages over other vitro vivo methods research. provides numerous examples on development new obtaining cultivation viruses. Among them sensitive reporter systems, design which can be promising tool diagnostics existing unknown viral infections. Cell characterized potential models virology developing diagnostic test-systems antiviral drugs. An important area application substrate production culture-derived vaccines. Another aspect also highlighted, study effect viruses host immune system or mechanisms immunopathogenesis It concluded remains near future one most practical scientific

Language: Английский

Citations

1