Efficacy of dispirotripiperazine PDSTP in a golden Syrian hamster model of SARS-CoV-2 infection DOI Creative Commons
Giuseppina Sanna, Olga Riabova, Elena Kazakova

et al.

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: March 10, 2025

The increasing incidence of viral pandemics calls for new small-molecule therapeutics beyond traditional approaches and targets. Dispirotripiperazine, composed two positively charged nitrogen atoms, represents an unusual scaffold in drug discovery campaigns, molecules based on it are known to prevent virus infection by disrupting early host–pathogen interactions. In this study, the adhesion-blocking dispirotripiperazine core compound PDSTP was evaluated against SARS-CoV-2 vitro vivo . We demonstrated that molecule acceptably active clinical isolates affecting stages cycle. a hamster model pneumonia, treatment resulted reduced loads lungs turbinates milder lung tissue lesions. Overall, these data support as preclinical candidate COVID-19.

Language: Английский

Syndecan-1 in liver pathophysiology DOI
Andrea Reszegi, Péter Tátrai, Eszter Regős

et al.

AJP Cell Physiology, Journal Year: 2022, Volume and Issue: 323(2), P. C289 - C294

Published: June 15, 2022

Syndecan-1 (SDC-1) is a heparan sulfate (HS)/chondroitin proteoglycan (PG) of the cell surface and extracellular matrix (ECM), which regulates broad spectrum physiological pathological processes such as proliferation, migration, inflammation, remodeling, wound healing, tumorigenesis. represents major PG liver, expressed by hepatocytes cholangiocytes, its elevated expression characteristic feature liver diseases. The highest syndecan-1 found in cirrhosis hepatocellular carcinoma (HCC) developed cirrhotic livers. In addition, being hepatitis C receptor, virus (HCV)-infected livers produce extremely large amounts syndecan-1. serum levels cleaved (shedded) domain have clinical significance, their increased concentration reflects on poor prognosis well cancer. vivo experiments confirmed that protects against early stages fibrogenesis mainly enhanced clearance transforming growth factor β1 (TGFβ1) thrombospondin-1 (THBS1) via circulation, hepatocarcinogenesis interfering with several signaling pathways enhancing cycle blockade. capable to hinder lipid metabolism ribosomal biogenesis induced cancer models. These observations together participation uptake viruses (e.g., HCV SARS-CoV-2) indicate central player pathologies.

Language: Английский

Citations

20
Is heparan sulfate a target for inhibition of RNA virus infection? DOI
Jiaxin Ling, Jinlin Li, Asifa Khan

et al.

AJP Cell Physiology, Journal Year: 2022, Volume and Issue: 322(4), P. C605 - C613

Published: Feb. 23, 2022

Heparan sulfate (HS) is a linear polysaccharide attached to core protein, forming heparan proteoglycans (HSPGs) that are ubiquitously expressed on the surface of almost all mammalian cells and extracellular matrix. HS orchestrates binding various signal molecules their receptors, thus regulating many biological processes, including homeostasis, metabolism, pathological processes. Due its wide distribution negatively charged properties, exploited by viruses as cofactor attach host cells. Therefore, inhibition interaction between virus proposed promising approach mitigate viral infection, SARS-CoV-2. In this review, we summarize manners with focus significant pathogenic RNA viruses, alphaviruses, flaviviruses, coronaviruses. We also provide an overview challenges may face when using mimetics antivirals for clinical treatment. More studies needed further understanding interplay both in vitro vivo, which will favor development specific antiviral inhibitors.

Language: Английский

Citations

19
Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade DOI Creative Commons
Alexandra P. M. Cloherty, Anusca G. Rader,

Kharishma S. Patel

et al.

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(1)

Published: March 23, 2023

SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after clearance. Despite vaccination and existing antiviral treatments, variants concern are still emerging circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies demonstrate an increased preference for entry via endocytic route. Alternative direct-acting antivirals, host-directed therapies interfere host mechanisms hijacked by viruses, enhance cell-mediated resistance reduced likelihood drug development. Here, we that autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents acquisition human intestinal epithelial cells autophagy-mediated BNIP3 mechanism. Strikingly, exhibited pan-antiviral activity against subvariants BA.2 at nanomolar potency, providing proof concept potential targeting autophagy machinery thwart infection current circulating subvariants. Furthermore, show limited virus-induced damage barrier function, affirming relevance manipulation avert permeability associated acute post-COVID-19 syndrome. Our findings underscore exploits dissemination indicate repurposed autophagy-based antivirals represent pertinent option boost protection ameliorate disease pathogenesis future concern.

Language: Английский

Citations

11
SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN DOI Creative Commons
Lieve E. H. van der Donk, Marta Bermejo‐Jambrina, John L. van Hamme

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(10), P. e1011735 - e1011735

Published: Oct. 16, 2023

SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are major factor in causing morbidity mortality, superinfections bacteria during COVID-19 often cause bacteremia sepsis. Aberrant immune might underlie increased sensitivity but the mechanisms remain unclear. Here we investigated whether directly suppresses bacteria. We studied functionality of human dendritic cells (DCs) towards variety bacterial triggers after exposure Spike (S) protein primary isolate (hCoV-19/Italy). Notably, pre-exposure DCs either S or led reduced type I interferon (IFN) cytokine response Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. interacted C-type lectin DC-SIGN and, notably, blocking antibodies restored IFN LPS. Moreover, kinase Raf-1 by small molecule inhibitor These results suggest that modulates DC function upon TLR4 triggering via DC-SIGN-induced pathway. data imply actively DC-SIGN, which account for higher mortality rates observed patients superinfections.

Language: Английский

Citations

11
Efficacy of dispirotripiperazine PDSTP in a golden Syrian hamster model of SARS-CoV-2 infection DOI Creative Commons
Giuseppina Sanna, Olga Riabova, Elena Kazakova

et al.

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: March 10, 2025

The increasing incidence of viral pandemics calls for new small-molecule therapeutics beyond traditional approaches and targets. Dispirotripiperazine, composed two positively charged nitrogen atoms, represents an unusual scaffold in drug discovery campaigns, molecules based on it are known to prevent virus infection by disrupting early host–pathogen interactions. In this study, the adhesion-blocking dispirotripiperazine core compound PDSTP was evaluated against SARS-CoV-2 vitro vivo . We demonstrated that molecule acceptably active clinical isolates affecting stages cycle. a hamster model pneumonia, treatment resulted reduced loads lungs turbinates milder lung tissue lesions. Overall, these data support as preclinical candidate COVID-19.

Language: Английский

Citations

0