scholarly journals Bithiazole Inhibitors of Phosphatidylinositol 4‐Kinase (PI4KIIIβ) as Broad‐Spectrum Antivirals Blocking the Replication of SARS‐CoV‐2, Zika Virus and Human Rhinoviruses

ChemMedChem ◽  
2021 ◽  
Author(s):  
Maria Grazia Martina ◽  
Ilaria Vicenti ◽  
Lisa Bauer ◽  
Emmanuele Crespan ◽  
Enrico Rango ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Zika Virus ◽  
Phosphatidylinositol 4

scholarly journals Front Cover: Bithiazole Inhibitors of Phosphatidylinositol 4‐Kinase (PI4KIIIβ) as Broad‐Spectrum Antivirals Blocking the Replication of SARS‐CoV‐2, Zika Virus, and Human Rhinoviruses (ChemMedChem 23/2021)

ChemMedChem ◽  
2021 ◽  
Vol 16 (23) ◽  
pp. 3495-3495
Author(s):  
Maria Grazia Martina ◽  
Ilaria Vicenti ◽  
Lisa Bauer ◽  
Emmanuele Crespan ◽  
Enrico Rango ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Zika Virus ◽  
Front Cover ◽  
Phosphatidylinositol 4

scholarly journals Fludarabine Inhibits Infection of Zika Virus, SFTS Phlebovirus, and Enterovirus A71

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 774
Author(s):  
Chengfeng Gao ◽  
Chunxia Wen ◽  
Zhifeng Li ◽  
Shuhan Lin ◽  
Shu Gao ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Zika Virus ◽  
Therapeutic Agent ◽  
Viral Infections ◽  
Rna Virus ◽  
Emerging Viruses ◽  
Enterovirus A71 ◽  
Ic50 Values ◽  
High Doses ◽  
Severe Fever

Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC50 values below 1 μM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.

scholarly journals Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

2017 ◽  
Vol 137 ◽  
pp. 14-22 ◽  
Author(s):  
Justin G. Julander ◽  
Venkatraman Siddharthan ◽  
Joe Evans ◽  
Ray Taylor ◽  
Kelsey Tolbert ◽  
...  
Keyword(s):  
Cell Culture ◽  
Mouse Model ◽  
Broad Spectrum ◽  
Zika Virus ◽  
Antiviral Compound

scholarly journals Labyrinthopeptins Exert Broad-Spectrum Antiviral Activity through Lipid-Binding-Mediated Virolysis

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Hans Prochnow ◽  
Katharina Rox ◽  
N. V. Suryanarayana Birudukota ◽  
Loreen Weichert ◽  
Sven-Kevin Hotop ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Host Cell ◽  
Broad Spectrum ◽  
Zika Virus ◽  
Kaposi's Sarcoma ◽  
Chikungunya Virus ◽  
Viral Infections ◽  
Kaposi’S Sarcoma ◽  
Membrane Lipid ◽  
Virus Zika

ABSTRACT To counteract the serious health threat posed by known and novel viral pathogens, drugs that target a variety of viruses through a common mechanism have attracted recent attention due to their potential in treating (re)emerging infections, for which direct-acting antivirals are not available. We found that labyrinthopeptins A1 and A2, the prototype congeners of carbacyclic lanthipeptides, inhibit the proliferation of diverse enveloped viruses, including dengue virus, Zika virus, West Nile virus, hepatitis C virus, chikungunya virus, Kaposi’s sarcoma-associated herpesvirus, cytomegalovirus, and herpes simplex virus, in the low micromolar to nanomolar range. Mechanistic studies on viral particles revealed that labyrinthopeptins induce a virolytic effect through binding to the viral membrane lipid phosphatidylethanolamine (PE). These effects are enhanced by a combined equimolar application of both labyrinthopeptins, and a clear synergism was observed across a concentration range corresponding to 10% to 90% inhibitory concentrations of the compounds. Time-resolved experiments with large unilamellar vesicles (LUVs) reveal that membrane lipid raft compositions (phosphatidylcholine [PC]/PE/cholesterol/sphingomyelin at 17:10:33:40) are particularly sensitive to labyrinthopeptins in comparison to PC/PE (90:10) LUVs, even though the overall PE amount remains constant. Labyrinthopeptins exhibited low cytotoxicity and had favorable pharmacokinetic properties in mice (half-life [t1/2] = 10.0 h), which designates them promising antiviral compounds acting by an unusual viral lipid targeting mechanism. IMPORTANCE For many viral infections, current treatment options are insufficient. Because the development of each antiviral drug is time-consuming and expensive, the prospect of finding broad-spectrum antivirals that can fight multiple, diverse viruses—well-known viruses as well as (re)emerging species—has gained attention, especially for the treatment of viral coinfections. While most known broad-spectrum agents address processes in the host cell, we found that targeting lipids of the free virus outside the host cell with the natural products labyrinthopeptin A1 and A2 is a viable strategy to inhibit the proliferation of a broad range of viruses from different families, including chikungunya virus, dengue virus, Zika virus, Kaposi’s sarcoma-associated herpesvirus, and cytomegalovirus. Labyrinthopeptins bind to viral phosphatidylethanolamine and induce virolysis without exerting cytotoxicity on host cells. This represents a novel and unusual mechanism to tackle medically relevant viral infections.

scholarly journals A Novel, Broad-Spectrum Inhibitor of Enterovirus Replication That Targets Host Cell Factor Phosphatidylinositol 4-Kinase IIIβ

2013 ◽  
Vol 57 (10) ◽  
pp. 4971-4981 ◽  
Author(s):  
Hilde M. van der Schaar ◽  
Pieter Leyssen ◽  
Hendrik J. Thibaut ◽  
Armando de Palma ◽  
Lonneke van der Linden ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Selection Process ◽  
Binding Pocket ◽  
Socioeconomic Impacts ◽  
Lipid Kinase ◽  
Resistance Selection ◽  
Phosphatidylinositol 4 ◽  
Kinase Activity Assay ◽  
Dose Dependent

ABSTRACTDespite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in anin vitrokinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.

scholarly journals Methylene blue is a potent and broad-spectrum inhibitor against Zika virus in vitro and in vivo

2020 ◽  
Vol 9 (1) ◽  
pp. 2404-2416
Author(s):  
Zhong Li ◽  
Yuekun Lang ◽  
Srilatha Sakamuru ◽  
Subodh Samrat ◽  
Nicole Trudeau ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Broad Spectrum ◽  
Zika Virus

scholarly journals Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus

Cell Reports ◽  
2017 ◽  
Vol 18 (3) ◽  
pp. 804-815 ◽  
Author(s):  
Keiko Rausch ◽  
Brent A. Hackett ◽  
Nathan L. Weinbren ◽  
Sophia M. Reeder ◽  
Yoel Sadovsky ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Zika Virus

scholarly journals Identification of Broad-Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6-Diaminopurine Scaffolds

ChemMedChem ◽  
2018 ◽  
Vol 13 (14) ◽  
pp. 1371-1376 ◽  
Author(s):  
Suzanne J. F. Kaptein ◽  
Paolo Vincetti ◽  
Emmanuele Crespan ◽  
Jorge I. Armijos Rivera ◽  
Gabriele Costantino ◽  
...  
Keyword(s):  
Virus Replication ◽  
Broad Spectrum ◽  
Zika Virus

Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology

2016 ◽  
Vol 60 (1) ◽  
pp. 100-118 ◽  
Author(s):  
Ivana Mejdrová ◽  
Dominika Chalupská ◽  
Pavla Plačková ◽  
Christin Müller ◽  
Michal Šála ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Chemical Biology ◽  
Rational Design ◽  
Antiviral Agents ◽  
Phosphatidylinositol 4
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