scholarly journals Strigolactone Analogs Are Promising Antiviral Agents for the Treatment of Human Cytomegalovirus Infection

2020 ◽  
Vol 8 (5) ◽  
pp. 703
Author(s):  
Matteo Biolatti ◽  
Marco Blangetti ◽  
Giulia D’Arrigo ◽  
Francesca Spyrakis ◽  
Paola Cappello ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Developed Countries ◽  
Promising Alternative ◽  
Late Protein ◽  
Potential Applications ◽  
Infected Cells

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impairing late protein expression. Moreover, we show that the SL-dependent induction of apoptosis in HCMV-infected cells is a contributing mechanism to SL antiviral properties. Overall, our results indicate that SLs may be a promising alternative to nucleoside analogs for the treatment of HCMV infections.

scholarly journals The Human Cytomegalovirus UL44 Protein Is a Substrate for the UL97 Protein Kinase

2003 ◽  
Vol 77 (14) ◽  
pp. 7720-7727 ◽  
Author(s):  
Paula M. Krosky ◽  
Moon-Chang Baek ◽  
Wan Jin Jahng ◽  
Imma Barrera ◽  
Robert J. Harvey ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Human Cytomegalovirus ◽  
Nucleoside Analogs ◽  
Wild Type Virus ◽  
Null Mutant ◽  
Natural Substrate ◽  
Wild Type ◽  
Two Dimensional Gel Electrophoresis ◽  
Infected Cells

ABSTRACT The human cytomegalovirus UL97 protein is an unusual protein kinase that is able to autophosphorylate and to phosphorylate certain exogenous substrates, including nucleoside analogs such as ganciclovir. However, no natural substrate of UL97 in infected cells has been identified. We report here that recombinant UL44 protein became radiolabeled when incubated with recombinant UL97 and [32P]ATP and that both proteins could be coimmunoprecipitated by an antibody that recognizes either protein. Subsequent studies showed that highly purified, recombinant UL97 phosphorylated purified, recombinant UL44. This phosphorylation occurred on serine and threonine residues and was sensitive to inhibition by maribavir and to a mutation that inactivates UL97 catalytic activity. Two-dimensional gel electrophoresis revealed the absence of specific phosphorylated forms of UL44 in immunoprecipitates from lysates of cells infected with a UL97 null mutant virus or with wild-type virus in the presence of maribavir. The results indicate that UL97 is sufficient to phosphorylate UL44 in vitro and is necessary for the normal phosphorylation of UL44 in infected cells. This strongly suggests that UL44 is a natural substrate of UL97.

scholarly journals Chloroquine inhibits Zika Virus infection in different cellular models

2016 ◽  
Author(s):  
Rodrigo Delvecchio ◽  
Luiza M Higa ◽  
Paula Pezzuto ◽  
Ana Luiza Valadão ◽  
Patrícia P Garcez ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Zika Virus ◽  
Antiviral Agents ◽  
Virus Production ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Cytotoxic Effects ◽  
Cellular Models ◽  
Infected Cells

SummaryZika virus (ZIKV) infectionin uteromight lead to microcephaly and other congenital defects. In adults, cases of Guillain-Barré syndrome and meningoencephalitis associated with ZIKV infection have been reported, and no specific therapy is available so far. There is urgency for the discovery of antiviral agents capable of inhibiting viral replication and its deleterious effects. Chloroquine is widely administered as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in VERO, human brain microvascular endothelial, and neural stem cells. We demonstratedin vitrothat chloroquine reduces the number of ZIKV-infected cells, virus production and cell death promoted by ZIKV infection without cytotoxic effects. Our results suggest that chloroquine is a promising candidate for ZIKV clinical trials, since it is already approved for clinical use and can be safely administered to pregnant woman.

scholarly journals Phosphorylation of β-d-Ribosylbenzimidazoles Is Not Required for Activity against Human Cytomegalovirus

2002 ◽  
Vol 46 (2) ◽  
pp. 478-486 ◽  
Author(s):  
Paula M. Krosky ◽  
Katherine Z. Borysko ◽  
M. Reza Nassiri ◽  
Rodrigo V. Devivar ◽  
Roger G. Ptak ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Dna Synthesis ◽  
Human Cytomegalovirus ◽  
High Performance ◽  
Selective Inhibitors ◽  
Viral Dna ◽  
Infected Cells ◽  
Hcmv Replication ◽  
Antiviral Nucleosides

ABSTRACT We have previously reported that 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) and its 2-bromo analog (2-bromo-5,6-dichloro-1-(β-d-ribofuranosy)benzimidazole [BDCRB]) are potent and selective inhibitors of human cytomegalovirus (HCMV) replication that block viral DNA maturation via HCMV gene products UL89 and UL56. To determine if phosphorylation is required for antiviral activity, the in vitro metabolism of BDCRB was examined and the antiviral activities of nonphosphorylatable 5′-deoxy analogs were determined. Reverse-phase high-performance liquid chromatography (HPLC) analysis of extracts from uninfected and HCMV-infected cells incubated with [3H]BDCRB revealed two major metabolites. Both were less polar than naturally occurring nucleoside monophosphates, but one peak coeluted with a BDCRB-5′-monophosphate (BDCRB-5′-MP) standard. Further analysis revealed, however, that neither metabolite partitioned with BDCRB-5′-MP on anion-exchange HPLC. Their retention patterns were not affected by incubation with alkaline phosphatase, thereby establishing that the compounds were not nucleoside 5′-monophosphates. Both compounds were detected in uninfected and HCMV-infected cells and in mouse live extracts, but neither has been identified. Like TCRB and BDCRB, the nonphosphorylatable 5′-deoxy analogs were potent and selective inhibitors of HCMV replication. The 5′-deoxy analogs maintained inhibition of HCMV replication upon removal of BDCRB, whereas an inhibitor of DNA synthesis did not. Similar to TCRB, its 5′-deoxy analog (5′-dTCRB) did not affect viral DNA synthesis, but 5′-dTCRB did inhibit viral DNA maturation to genome-length units. Additionally, virus isolates resistant to TCRB were also resistant to 5′-dTCRB and the 5′-deoxy analog of BDCRB. Taken together, these results confirm that TCRB, BDCRB, and their 5′-deoxy analogs have common mechanisms of action and establish that these benzimidazole ribonucleosides, unlike other antiviral nucleosides, do not require phosphorylation at the 5′ position for antiviral activity.

scholarly journals The New Generation hDHODH Inhibitor MEDS433 Hinders the In Vitro Replication of SARS-CoV-2 and OtherHuman Coronaviruses

2021 ◽  
Vol 9 (8) ◽  
pp. 1731
Author(s):  
Arianna Calistri ◽  
Anna Luganini ◽  
Barbara Mognetti ◽  
Elizabeth Elder ◽  
Giulia Sibille ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
De Novo ◽  
Antiviral Agents ◽  
Embryonic Stem ◽  
Potential Candidate ◽  
In Vitro Replication ◽  
Infected Cells ◽  
New Generation

Although coronaviruses (CoVs) have long been predicted to cause zoonotic diseases and pandemics with high probability, the lack of effective anti-pan-CoVs drugs rapidly usable against the emerging SARS-CoV-2 actually prevented a promptly therapeutic intervention for COVID-19. Development of host-targeting antivirals could be an alternative strategy for the control of emerging CoVs infections, as they could be quickly repositioned from one pandemic event to another. To contribute to these pandemic preparedness efforts, here we report on the broad-spectrum CoVs antiviral activity of MEDS433, a new inhibitor of the human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of the de novo pyrimidine biosynthesis pathway. MEDS433 inhibited the in vitro replication of hCoV-OC43 and hCoV-229E, as well as of SARS-CoV-2, at low nanomolar range. Notably, the anti-SARS-CoV-2 activity of MEDS433 against SARS-CoV-2 was also observed in kidney organoids generated from human embryonic stem cells. Then, the antiviral activity of MEDS433 was reversed by the addition of exogenous uridine or the product of hDHODH, the orotate, thus confirming hDHODH as the specific target of MEDS433 in hCoVs-infected cells. Taken together, these findings suggest MEDS433 as a potential candidate to develop novel drugs for COVID-19, as well as broad-spectrum antiviral agents exploitable for future CoVs threats.

Synthesis and Antiviral Activities of 3-Aralkyl-Thiomethylimidazo[1,2-b]Pyridazine Derivatives

2003 ◽  
Vol 14 (4) ◽  
pp. 177-182 ◽  
Author(s):  
Christophe Galtier ◽  
Sylvie Mavel ◽  
Robert Snoeck ◽  
Graciela Andreï ◽  
Christophe Pannecouque ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Varicella Zoster Virus ◽  
Human Cytomegalovirus ◽  
Antiviral Agents ◽  
Varicella Zoster ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Pyridazine Derivatives

The synthesis of novel substituted 3-aralkylth-iomethylimidazo[1,2- b]pyridazines is reported. All of the synthesized compounds are devoid of antiviral activity against the replication of human immunodeficiency virus. However, compounds 6-chloro-8-methyl-3-phenethylthioimidazo[1,2- b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2- b]pyridazine are potent inhibitors of the replication of human cytomegalovirus in vitro, while compounds 6-chloro-2-methyl-3-benzylthiomethylimidazo[1,2- b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2- b]pyridazineare inhibitors of the replication of varicella-zoster virus. The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents.

scholarly journals Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 196
Author(s):  
Sara Artusi ◽  
Emanuela Ruggiero ◽  
Matteo Nadai ◽  
Beatrice Tosoni ◽  
Rosalba Perrone ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Dna Replication ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Herpes Simplex Virus 1 ◽  
Tem Analysis ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Different in Vivo Models

2000 ◽  
Vol 11 (1) ◽  
pp. 51-59 ◽  
Author(s):  
Olaf Weber ◽  
Jürgen Reefschläger ◽  
Helga Rübsamen-Waigmann ◽  
Siegfried Raddatz ◽  
Matthias Hesseling ◽  
...  
Keyword(s):  
Animal Models ◽  
Antiviral Activity ◽  
Clinical Isolate ◽  
Human Cytomegalovirus ◽  
Murine Cytomegalovirus ◽  
Human Tissues ◽  
In Vivo Models ◽  
Peptide Aldehydes

Novel peptide aldehydes (PAs) were identified as potent inhibitors of human cytomegalovirus (HCMV) in vitro. Although these compounds were highly effective against HCMV, they did not exhibit any activity against murine cytomegalovirus (MCMV). The purpose of this study was to test the antiviral activity of PA 8 as a representative of this novel class of inhibitors against HCMV in vivo. Because of the strict species specificity of HCMV we had to use two artificial animal models. In the first model, HCMV-infected human cells were entrapped into agarose plugs and transplanted into mice. In the second model, SCID mice were transplanted with human tissues that were subsequently infected with a clinical isolate of HCMV. In these two models the antiviral activity of PA 8 was clearly demonstrated, ganciclovir only being slightly superior in its in vivo antiviral activity.

scholarly journals Synthetic Peptides as a Promising Alternative to Control Viral Infections in Atlantic Salmon

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 600 ◽  
Author(s):  
Constanza Cárdenas ◽  
Fanny Guzmán ◽  
Marisela Carmona ◽  
Cristian Muñoz ◽  
Luis Nilo ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Infections ◽  
Antiviral Agents ◽  
In Silico Analysis ◽  
Infectious Pancreatic Necrosis Virus ◽  
Fish Cell ◽  
Promising Alternative ◽  
Anemia Virus

Viral infections in salmonids represent an ongoing challenge for the aquaculture industry. Two RNA viruses, the infectious pancreatic necrosis virus (IPNV) and the infectious salmon anemia virus (ISAV), have become a latent risk without healing therapies available for either. In this context, antiviral peptides emerge as effective and relatively safe therapeutic molecules. Based on in silico analysis of VP2 protein from IPNV and the RNA-dependent RNA polymerase from ISAV, a set of peptides was designed and were chemically synthesized to block selected key events in their corresponding infectivity processes. The peptides were tested in fish cell lines in vitro, and four were selected for decreasing the viral load: peptide GIM182 for IPNV, and peptides GIM535, GIM538 and GIM539 for ISAV. In vivo tests with the IPNV GIM 182 peptide were carried out using Salmo salar fish, showing a significant decrease of viral load, and proving the safety of the peptide for fish. The results indicate that the use of peptides as antiviral agents in disease control might be a viable alternative to explore in aquaculture.

scholarly journals Recombinant Green Fluorescent Protein-Expressing Human Cytomegalovirus as a Tool for Screening Antiviral Agents

2000 ◽  
Vol 44 (6) ◽  
pp. 1588-1597 ◽  
Author(s):  
Manfred Marschall ◽  
Martina Freitag ◽  
Sigrid Weiler ◽  
Gabriele Sorg ◽  
Thomas Stamminger
Keyword(s):  
Green Fluorescent Protein ◽  
Human Cytomegalovirus ◽  
Fluorescent Protein ◽  
Antiviral Agents ◽  
Inhibitory Effects ◽  
Plaque Reduction Assay ◽  
Human Fibroblast Cultures ◽  
Antiviral Activities ◽  
Green Fluorescent

ABSTRACT A recombinant human cytomegalovirus (AD169-GFP) expressing green fluorescent protein was generated by homologous recombination. Infection of human fibroblast cultures with AD169-GFP virus produced stable and readily detectable amounts of GFP signals which were quantitated by automated fluorometry. Hereby, high levels of sensitivity and reproducibility could be achieved, compared to those with the conventional plaque reduction assay. Antiviral activities were determined for four reference compounds as well as a set of putative novel cytomegalovirus inhibitors. The results obtained were exactly in line with the known characteristics of reference compounds and furthermore revealed distinct antiviral activities of novel in vitro inhibitors. The fluorometric data could be confirmed by GFP-based flow cytometry and fluorescence microscopy. In addition, laboratory virus variants derived from the recombinant AD169-GFP virus provided further possibilities for study of the characteristics of drug resistance. The GFP-based antiviral assay appeared to be very reliable for measuring virus-inhibitory effects in concentration- and time-dependent fashions and might also be adaptable for high-throughput screenings of cytomegalovirus-specific antiviral agents.

Sign in / Sign up

Export Citation Format

Share Document