scholarly journals Inhibition of Cyclin-Dependent Kinase 1 by Purines and Pyrrolo[2,3-d]Pyrimidines Does Not Correlate with Antiviral Activity

2002 ◽  
Vol 46 (8) ◽  
pp. 2470-2476 ◽  
Author(s):  
David L. Evers ◽  
Julie M. Breitenbach ◽  
Katherine Z. Borysko ◽  
Leroy B. Townsend ◽  
John C. Drach
Keyword(s):  
Antiviral Activity ◽  
Early Stage ◽  
Nucleoside Analogs ◽  
Cyclin B ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Hcmv Replication ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We have previously shown that a series of nonnucleoside pyrrolo[2,3-d]pyrimidines selectively inhibit the replication of herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). These compounds act at the immediate-early or early stage of HCMV replication and have antiviral properties somewhat similar to those of roscovitine and olomoucine, specific inhibitors of cyclin-dependent kinases (cdks). In the present study we examine the hypothesis that pyrrolo[2,3-d]pyrimidines exert their antiviral effects by inhibition of cellular cdks. Much higher concentrations of a panel of pyrrolo[2,3-d]pyrimidine nucleoside analogs with antiviral activity were required to inhibit recombinant cdk1/cyclin B compared to the submicromolar concentrations required to inhibit HCMV and HSV-1 replication. 4,6-Diamino-5-cyano-7-(2-phenylethyl)pyrrolo[2,3-d]pyrimidine (compound 1369) was the best inhibitor of cdk1 and cyclin B, with a 50% inhibitory concentration (IC50; 14 μM) similar to that of roscovitine; it was competitive with respect to ATP (Ki = 14 μM). The potency of compound 1369 against cdk1 and cyclin B was similar to its cytotoxicity (IC50s, 32 to 100 μM) but not its antiviral efficacy (IC50s, 0.02 to 0.3 μM). Thus, our results indicated the null hypothesis. In contrast, roscovitine was only weakly active against HSV-1 (IC50, 38 μM) and HCMV (IC50, 40 μM). These values were similar to those derived by cytotoxicity and cell growth inhibition assays, thereby suggesting that roscovitine is not a selective antiviral. Therefore, we propose that inhibition of cdk1 and cyclin B is not responsible for selective antiviral activity and that pyrrolo[2,3-d]pyrimidines constitute novel pharmacophores which compete with ATP to inhibit cdk1 and cyclin B.

scholarly journals Activity of Penciclovir in Combination with Azido-Thymidine, Ganciclovir, Acyclovir, Foscarnet and Human Interferons against Herpes Simplex Virus Replication in Cell Culture

1992 ◽  
Vol 3 (2) ◽  
pp. 85-94 ◽  
Author(s):  
D. Sutton ◽  
J. Taylor ◽  
T. H. Bacon ◽  
M. R. Boyd
Keyword(s):  
Cell Culture ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Antiviral Agents ◽  
High Concentrations ◽  
Simplex Virus ◽  
Hsv 1

Combinations of penciclovir (PCV) with other antiviral agents (acyclovir, ACV; ganciclovir, GCV; foscarnet, PFA; azido-thymidine, AZT) or with human interferons (HulFN-α,β,γ) were tested for inhibitory activity against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) in cell culture. The antiviral interactions observed between combinations of PCV with ACV or GCV were purely additive. Combinations of PCV with HulFNs demonstrated highly synergistic anti-herpesvirus activity; some synergy was also detected between PCV and PFA against HSV-1. High concentrations of AZT inhibited the antiviral activity of PCV; this antagonism was competitive. In more detailed studies it was demonstrated that high concentrations of AZT also inhibited the antiviral activity of ACV, and that ACV was more sensitive to this antagonism than PCV. It was concluded that the antagonism was unlikely to have clinical significance.

scholarly journals Viral UL8 Is Involved in the Antiviral Activity of Oleanolic Acid Against HSV-1 Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Tianhao Shan ◽  
Ju Ye ◽  
Jiaoyan Jia ◽  
Zhaoyang Wang ◽  
Yuzhou Jiang ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Antiviral Activity ◽  
Oleanolic Acid ◽  
Early Stage ◽  
Skin Lesions ◽  
Therapeutic Drug ◽  
Potential Candidate ◽  
Pentacyclic Triterpenoid ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) is highly prevalent in humans and can cause severe diseases, especially in immunocompromised adults and newborns, such as keratitis and herpes simplex encephalitis. At present, the clinical therapeutic drug against HSV-1 infection is acyclovir (ACV), and its extensive usage has led to the emergence of ACV-resistant strains. Therefore, it is urgent to explore novel therapeutic targets and anti-HSV-1 drugs. This study demonstrated that Oleanolic acid, a pentacyclic triterpenoid widely existing in natural product, had strong antiviral activity against both ACV-sensitive and -resistant HSV-1 strains in different cells. Mechanism studies showed that Oleanolic acid exerted its anti-HSV-1 activity in the immediate early stage of infection, which involved the dysregulation of viral UL8, a component of viral helicase-primase complex critical for viral replication. In addition, Oleanolic acid significantly ameliorated the skin lesions in an HSV-1 infection mediated zosteriform model. Together, our study suggested that Oleanolic acid could be a potential candidate for clinical therapy of HSV-1 infection-related diseases.

scholarly journals A Polyphenol Rich Extract from Solanum melongena L. DR2 Peel Exhibits Antioxidant Properties and Anti-Herpes Simplex virus Type 1 Activity In Vitro

2018 ◽  
Author(s):  
Antonella Di Sotto ◽  
Silvia Di Giacomo ◽  
Donatella Amatore ◽  
Marcello Locatelli ◽  
Annabella Vitalone ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antioxidant Properties ◽  
Solanum Melongena ◽  
Vero Cells ◽  
Host Cells ◽  
Reducing Conditions ◽  
Simplex Virus ◽  
Hsv 1

DR2B and DR2C extracts, from peel of commercially and physiologically ripe eggplants, were studied for the antioxidative cytoprotective properties and anti-HSV-1 activity, in line with the evidence that several antioxidants can impair viral replication by maintaining reducing conditions into the host cells. The antioxidative cytoprotective effects against tBOOH-induced damage was assessed in Caco2 cells, while the antiviral activity was studied in Vero cells; phenolic and anthocyanin fingerprint was characterized by integrated phytochemical methods. Results highlighted different compositions of the extracts, with chlorogenic acid and delphinidin-3-rutinoside as the major constituents; other peculiar phytochemicals were also identified. DR2C resulted able to partly counteract the tBOOH-induced cytotoxicity, with a remarkable lowering of lactate metabolism under both normoxia and hypoxia. DR2B and DR2C reduced ROS production, possessed scavenging and chelating properties. Interestingly, DR2C increased intracellular GSH levels. Furthermore, DR2C inhibited the HSV-1 replication when added for 24 h after viral adsorption, as also confirmed by the reduction of many viral proteins expression. Since DR2C was able to reduce NOX4 expression during HSV-1 infection, its antiviral activity may be correlated to its antioxidant properties. Although further studies are needed to better characterize DR2C activity, the results suggest this extract as a promising new anti-HSV-1 agent.

Scopadulciol is an Inhibitor of Herpes Simplex Virus Type 1 and a Potentiator of Aciclovir

1996 ◽  
Vol 7 (2) ◽  
pp. 79-85 ◽  
Author(s):  
Kyoko Hayashi ◽  
Toshimitsu Hayashi
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Virus Type ◽  
Hela Cells ◽  
Herpes Simplex Virus Type ◽  
Infected Cells ◽  
Simplex Virus ◽  
Hsv 1

The antiviral activity of scopadulciol (SDC), a tetracyclic diterpenoid with a chemical structure related to that of aphidicolin, isolated from Scoparia dulcis, was studied in vitro against herpes simplex virus type 1 (HSV-1). SDC was found to inhibit the virus replication as shown by reduction of virus production. The action was not due to the inhibition of viral DNA polymerase activity and virus penetration, but might involve, at least in part, a virucidal effect. SDC did not suppress the viral protein synthesis of infected cells when added at an early stage of HSV-1 replication, but did when added later. When aciclovir (ACV) and SDC were evaluated in combination for antiviral activity against HSV-1 replication and cytotoxicity, these drugs inhibited viral replication in HeLa cells synergistically, but the same combination did not produce synergistic cytotoxicity in HeLa cells. Studies of the deoxynucleotide pool sizes revealed that SDC increased the intracellular dNTP pools and ACV triphosphate level significantly in infected cells when the cells were treated with the combination. These results could account for the synergistic action between SDC and ACV.

scholarly journals Phytochemistry, cytotoxicity and antiviral activity of Catharanthus roseus

2020 ◽  
Author(s):  
Noor Zarina Abd Wahab ◽  
Aziah Azizul ◽  
Nazlina Ibrahim
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Catharanthus Roseus ◽  
Mtt Assay ◽  
Crude Extract ◽  
Pre Treatment ◽  
Simplex Virus ◽  
Hsv 1

Background and Objectives: Catharanthus roseus is generally used to treat many diseases in folklore remedies. The present study is aimed at determining phytochemical constituents, cytotoxicity and antiviral activities for crude extract of the plant. Materials and Methods: The whole plant of C. roseus was extracted using methanol extraction method. Phytochemical qualitative screening was carried out for C. roseus extract according to standard procedures used to test for the presence of alkaloid, saponin, terpenoid and steroid. Cytotoxicity was assessed using 3-(4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide (MTT) assay. Plaque reduction assays were carried out to evaluate the antiviral activity of C. roseus extract against herpes simplex virus type 1 (HSV-1). These include post-treatment, pre-treatment and virucidal assays. Results: C. roseus extract contain secondary metabolites such as alkaloid, saponin and terpenoid but does not contain steroid. Cytotoxicity screening against Vero cells using MTT assay showed that the CC50 values for crude extract of C. roseus was 0.5 mg/mL. The extract prepared from C. roseus possesses phytochemical compound that was non-cytotoxic to the cell with potential antiviral activity. Plaque reduction assays against herpes simplex virus type 1 (HSV-1) showed that the selective indices (SI = CC50 / EC50) of C. roseus extract in post-treatment, pre-treatment and virucidal assays were 36, 20 and 4.7 respectively. The results revealed that the extract prepared from C. roseus possesses phytochemical compound that was non-cytotoxic to the cell with potential antiviral activity. Conclusion: This study showed that C. roseus extract has promising potential to be explored as anti-HSV-1 agent regardless of the mode of treatment.

scholarly journals Pharmacological Cyclin-Dependent Kinase Inhibitors Inhibit Replication of Wild-Type and Drug-Resistant Strains of Herpes Simplex Virus and Human Immunodeficiency Virus Type 1 by Targeting Cellular, Not Viral, Proteins

2002 ◽  
Vol 76 (15) ◽  
pp. 7874-7882 ◽  
Author(s):  
Luis M. Schang ◽  
Andrew Bantly ◽  
Marie Knockaert ◽  
Farida Shaheen ◽  
Laurent Meijer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Viral Proteins ◽  
Cyclin Dependent Kinase ◽  
Immunodeficiency Virus ◽  
Simplex Virus ◽  
Hiv 1 ◽  
Hsv 1

ABSTRACT Pharmacological cyclin-dependent kinase (cdk) inhibitors (PCIs) block replication of several viruses, including herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus type 1 (HIV-1). Yet, these antiviral effects could result from inhibition of either cellular cdks or viral enzymes. For example, in addition to cellular cdks, PCIs could inhibit any of the herpesvirus-encoded kinases, DNA replication proteins, or proteins involved in nucleotide metabolism. To address this issue, we asked whether purine-derived PCIs (P-PCIs) inhibit HSV and HIV-1 replication by targeting cellular or viral proteins. P-PCIs inhibited replication of HSV-1 and -2 and HIV-1, which require cellular cdks to replicate, but not vaccinia virus or lymphocytic choriomeningitis virus, which are not known to require cdks to replicate. P-PCIs also inhibited strains of HSV-1 and HIV-1 that are resistant to conventional antiviral drugs, which target viral proteins. In addition, the anti-HSV effects of P-PCIs and a conventional antiherpesvirus drug, acyclovir, were additive, demonstrating that the two drugs act by distinct mechanisms. Lastly, the spectrum of proteins that bound to P-PCIs in extracts of mock- and HSV-infected cells was the same. Based on these observations, we conclude that P-PCIs inhibit virus replication by targeting cellular, not viral, proteins.

Inhibition of Herpes Simplex Virus by Polyamines

2009 ◽  
Vol 20 (2) ◽  
pp. 87-98 ◽  
Author(s):  
Ira Yudovin-Farber ◽  
Irina Gurt ◽  
Ronen Hope ◽  
Abraham J Domb ◽  
Ehud Katz
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Clinical Investigation ◽  
Host Cells ◽  
Direct Exposure ◽  
Simplex Virus ◽  
Hsv 1

Background: Herpes simplex virus (HSV) establishes latent infection in humans with periodic reactivation. Acyclovir, valacyclovir and foscarnet are in medical use today against HSV type-1 (HSV-1) and type-2 (HSV-2), inhibiting the DNA synthesis of the viruses. Additional drugs that will affect the growth of these viruses by other mechanisms and also decrease the frequency of appearance of drug-resistant mutants are required. Methods: Cationic polysaccharides were synthesized by conjugation of various oligoamines to oxidized polysaccharides by reductive amination. Polycations of dextran, pullulan and arabinogalactan were grafted with oligoamines of 2–4 amino groups forming Schiff-base imine-based conjugates followed by reduction with borohydride to obtain the stable amine-based conjugate. Evaluation of toxicity to BS-C-1 cells and antiviral activity against HSV-1 and HSV-2 of the different compounds was performed in vitro by a semiquantitative assay. A quantitative study with a selected compound followed. Results: Structure–activity relationship studies showed that the nature of the grafted oligoamine of the polycation plays an essential role in the antiviral activity against HSV-1 and HSV-2. Dextran-propan-1,3-diamine (DPD) was found to be the most potent of all the compounds examined. DPD did not decrease the infectivity of HSV upon direct exposure to the virions. The growth of HSV was significantly inhibited when DPD was added to the host cells 1 h prior to infection, thus preventing the adsorption and penetration of the virus into the cells. Conclusions: Our in vitro data warrant clinical investigation. DPD could have an advantage as a topical application in combination therapy of HSV lesions.

scholarly journals Synthesis and Screening of Anti-HSV-1 Activity of Thioglucoside Derivatives of Natural Polyhydroxy-1,4-Naphthoquinones

2019 ◽  
Vol 14 (6) ◽  
pp. 1934578X1986067 ◽  
Author(s):  
Sergey G. Polonik ◽  
Natalia V. Krylova ◽  
Galina G. Kompanets ◽  
Olga V. Iunikhina ◽  
Yuri E. Sabutski
Keyword(s):  
Antiviral Activity ◽  
Radical Scavenging ◽  
Effective Inhibition ◽  
Infected Cells ◽  
Virucidal Effect ◽  
Simplex Virus ◽  
Derivatives Of ◽  
Hsv 1

Four 1,4-naphthoquinone dithioglucoside derivatives based on natural polyhydroxy-1,4-naphthoquinones were synthesized. These thioglucosides were screened for their antiradical and antiviral activity in vitro. Antiradical activity of tested compounds was determined by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. The anti-herpes simplex virus type 1 (anti-HSV-1) activity of thioglucosides was analyzed by the cytopathic effect inhibition assay and mode of antiviral action was determined by the addition of the tested compounds to uninfected cells, to the virus prior to infection, or to herpes-infected cells. Most effective inhibition of HSV-1 replication was observed at pretreatment of virus by the compounds (direct virucidal effect). The dithioglucoside conjugate with the single β-OH group and lipophilic ethyl substituent in naphthoquinone core showed the greatest antiviral activity.

scholarly journals Pink Cedar (Acrocarpus fraxinifolius): its prophylactic role against APAP–induced organs toxicity in rats and its antiviral activity against Herpes simplex virus type 1

2018 ◽  
Author(s):  
Eman Ali Abd El-Ghffar ◽  
Alaa Barakat ◽  
Zenab Ali Torky
Keyword(s):  
Antiviral Activity ◽  
Early Stage ◽  
Vero Cells ◽  
Male Rats ◽  
Protective Effects ◽  
Virus Attachment ◽  
Anti Oxidant ◽  
Simplex Virus ◽  
Toxic Concentrations ◽  
Hsv 1

AbstractThe possible protective effects of n-hexane extract Acrocarpus fraxinifolius leaves (nHEAFL) were assessed against the APAP–induced organ toxicity in male rats. Also, the content of polyphenols extracted from AFL was studied, and their relationship with antioxidant activity was investigated. nHEAFL was tested for cytotoxicity on Vero cell line, with reference to IC50, and other non-toxic concentrations of all the extracts. The antiviral activity against HSV-1 for all non-toxic concentrations of the extract was determined using plaque reduction assay. It was found that nHEAF showed a reduction of serum hepatic/renal cellular toxicity and cellular lipid peroxidation in kidney, spleen & heart, as well as enhanced cellular anti–oxidant defense system in tissues. Also, our results revealed that the inhibitory activity of the HSV-1 virus was dose dependent on the polyphenol content of the examined extract. The minimum inhibitory concentration (MIC) for the nHEAF extract was determined as well as the EC50 and SI. Calculated SI showed promising value for the nHEAFL, and hence can be used as therapeutic medication for HSV-1. Direct contact between the HSV-1 and the examined extract in cell-free assay system showed different degrees of virucidal activity depending on the polyphenolic content of these extracts. In order to study other possible mode of action, Vero cells were treated with the examined extracts before, during, and after virus infection to give an insight on the interference of the extract in each step in the virus life cycle. In conclusion, nHEAFL showed a remarkable organs protective effect against APAP–induced organs toxicity in rats. Also, examined extracts exhibited the antiviral activity against HSV-1 via blocking of the virus attachment and penetration and inhibition of the early stage of viral replications.

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