INTRODUCTION AND AIM: Infections caused by herpes simplex viruses (HSV) are frequent in the human population. Because of the widespread use of long-term treatment or prophylaxis by anti-herpetic antivirals in various specific medical contexts (immunosuppression, recurrent infections), the level of antiviral resistance is increasing. According to previous studies, there is a low resistance level in immunocompetent populations but a relatively high level in populations with immunodeficiency. However, there has been no study from the Czech Republic. This study presents results of a single-centre retrospective study from the Czech Republic. MATERIALS AND METHODS: Deep frozen DNA from patients with suspected clinical antiviral failure over a long time period (2009-2016) - a total of 15 isolates of HSV1 and seven of HSV2 - were examined for the presence of mutations associated with antiviral resistance. Sequence analysis was performed using an ABI PRISM 3500xL Genetic Analyzer (Applied Biosystems®). RESULTS: There were no mutations associated with resistance to antivirals inside the UL23 gene in HSV1 isolates. However, resistant mutation D672N (nucleotide change G2014A) was found inside the UL30 gene in seven of the isolates. One mutation associated with resistance to acyclovir (M183stop) was found inside the UL23 gene in one HSV2 isolate. Resistant mutation E678G (nucleotide change A2033G) was identified inside the UL30 gene in six of the HSV2 isolates. CONCLUSIONS: This study confirmed the presence of resistance mutations within the Czech population, but it will be necessary to examine a higher number of isolates for further conclusions.
- Klíčová slova
- Antiviral resistance, Herpes simplex virus, Sequencing,
- MeSH
- acyklovir farmakologie MeSH
- antivirové látky farmakologie MeSH
- DNA-dependentní DNA-polymerasy genetika MeSH
- exodeoxyribonukleasy genetika MeSH
- herpes simplex farmakoterapie virologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- mutace MeSH
- retrospektivní studie MeSH
- Simplexvirus účinky léků genetika MeSH
- terapie neúspěšná MeSH
- virová léková rezistence genetika MeSH
- virové proteiny genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- acyklovir MeSH
- antivirové látky MeSH
- DNA polymerase, Simplexvirus MeSH Prohlížeč
- DNA-dependentní DNA-polymerasy MeSH
- exodeoxyribonukleasy MeSH
- virové proteiny MeSH
Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC50: 0.96 μg/mL; selectivity index CC50/IC50: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC50: 1.92 μg/mL; selectivity index CC50/IC50: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC50: 0.73 μg/mL; selectivity index CC50/EC50: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC50: 1.75 μg/mL; selectivity index CC50/EC50: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α.
- Klíčová slova
- Eucalyptus, HSV-1, HSV-2, IL-1β, NF-κB/AP-1, ROS, TNF-α, anti-inflammatory, antibacterial, antiherpetic,
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- antiflogistika chemie farmakologie MeSH
- antiinfekční látky chemie farmakologie MeSH
- antioxidancia metabolismus MeSH
- antivirové látky chemie farmakologie MeSH
- buněčné linie MeSH
- Cercopithecus aethiops MeSH
- cytokiny metabolismus MeSH
- Eucalyptus chemie MeSH
- herpes simplex metabolismus virologie MeSH
- lidé MeSH
- NF-kappa B metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rostlinné extrakty chemie farmakologie MeSH
- Simplexvirus účinky léků fyziologie MeSH
- transkripční faktor AP-1 metabolismus MeSH
- Vero buňky MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibakteriální látky MeSH
- antiflogistika MeSH
- antiinfekční látky MeSH
- antioxidancia MeSH
- antivirové látky MeSH
- cytokiny MeSH
- NF-kappa B MeSH
- reaktivní formy kyslíku MeSH
- rostlinné extrakty MeSH
- transkripční faktor AP-1 MeSH
New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC50's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.
- Klíčová slova
- 5-Azacytosine, Acyclic nucleoside phosphonates, Antivirals, HPMP-5-azaC, Open-ring, PME-azaC, PMEO-DAPy, Phosphonate, Prodrug,
- MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buněčné linie MeSH
- Cytomegalovirus účinky léků MeSH
- lidé MeSH
- organofosfonáty chemická syntéza chemie farmakologie MeSH
- prekurzory léčiv chemická syntéza chemie farmakologie MeSH
- pyrimidinové nukleosidy chemie MeSH
- Simplexvirus účinky léků MeSH
- virus varicella zoster účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antivirové látky MeSH
- organofosfonáty MeSH
- prekurzory léčiv MeSH
- pyrimidinové nukleosidy MeSH
Series of novel acyclic nucleoside phosphonates (ANPs) with various nucleobases and 2-(2-phosphonoethoxy)ethyl (PEE) chain bearing various substituents in β-position to the phosphonate moiety were prepared. The influence of structural alternations on antiviral activity was studied. Several derivatives exhibit antiviral activity against HIV and vaccinia virus (middle micromolar range), HSV-1 and HSV-2 (lower micromolar range) and VZV and CMV (nanomolar range), although the parent unbranched PEE-ANPs are inactive. Adenine as a nucleobase and the methyl group attached to the PEE chain proved to be a prerequisite to afford pronounced antiviral activity.
- MeSH
- antivirové látky chemická syntéza chemie farmakologie MeSH
- buněčné linie MeSH
- herpes simplex farmakoterapie MeSH
- HIV infekce farmakoterapie MeSH
- HIV účinky léků MeSH
- lidé MeSH
- myši MeSH
- nukleosidy chemická syntéza chemie farmakologie MeSH
- organofosfonáty chemická syntéza chemie farmakologie MeSH
- Simplexvirus účinky léků MeSH
- vakcínie farmakoterapie MeSH
- viabilita buněk účinky léků MeSH
- virové nemoci farmakoterapie MeSH
- virus vakcinie účinky léků MeSH
- viry účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antivirové látky MeSH
- nukleosidy MeSH
- organofosfonáty MeSH
New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir.
- MeSH
- adenin analogy a deriváty chemie MeSH
- antivirové látky chemická syntéza chemie toxicita MeSH
- cidofovir MeSH
- Cytomegalovirus účinky léků MeSH
- cytosin analogy a deriváty chemie MeSH
- HIV účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- organofosfonáty chemie MeSH
- prekurzory léčiv chemická syntéza chemie toxicita MeSH
- Simplexvirus účinky léků MeSH
- virus varicella zoster účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adefovir MeSH Prohlížeč
- adenin MeSH
- antivirové látky MeSH
- cidofovir MeSH
- cytosin MeSH
- organofosfonáty MeSH
- prekurzory léčiv MeSH
BACKGROUND: Despite of prophylactic antiviral therapy, latent HSV may be reactivated in bone marrow transplant (BMT) recipients and cause serious disease. Rapid diagnosis of HSV infection is needed to prompt institution of appropriate therapy. OBJECTIVES: We report a case of the allogenic BMT recipient, who developed ulcerative esophagitis which progressed to generalized HSV infection and graft versus host reaction (GVHR).We consider several diagnostic approaches to detection of active HSV infection in this patient. STUDY DESIGN: Polymerase chain reaction (PCR) was used to detect HSV DNA in esophageal biopsy specimens and peripheral leukocytes (PBL). Isolation of HSV in tissue culture was performed to prove infectious virus in swabs from mucocutaneous lesions or in PBL. RESULTS: Using PCR, HSV DNA was detected in peripheral leukocytes of the patient who had developed generalized HSV infection accompanied with hepatosplenomegaly and hepatitis. At that time, a fully infectious ACV-resistant HSV was isolated from his PBL. On the other hand, HSV DNA was not detected in PBL of other BMT-recipients with skin- or organ-localized infection. CONCLUSIONS: Presence of HSV-DNA in PBL of BMT recipients can signalize generalized HSV infection. Isolation of HSV from PBL by cocultivation with human fibroblasts can be used as an alternative diagnostic approach in these patients.
- MeSH
- acyklovir farmakologie MeSH
- antibiotická rezistence MeSH
- antivirové látky farmakologie MeSH
- biopsie MeSH
- DNA virů analýza MeSH
- dospělí MeSH
- ezofágus virologie MeSH
- herpes simplex virologie MeSH
- leukocyty virologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- polymerázová řetězová reakce MeSH
- Simplexvirus účinky léků genetika izolace a purifikace MeSH
- transplantace kostní dřeně škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acyklovir MeSH
- antivirové látky MeSH
- DNA virů MeSH
Synthesis of the major DNA-binding protein (ICP8) was investigated in primary rabbit kidney (RK) and Vero cells infected with the syncytial (syn) strain HSZP or with the non-syn strain KOS of herpes simplex virus type 1 (HSV-1). Results showed the following: 1. In contrast to strain KOS, the rate of viral polypeptide synthesis was accelerated in Vero cells infected with strain HSZP. The ICP8 could be detected in the nuclei of cells by one hour post-infection (hr p. i.) where it became associated with the viral DNA (DNase sensitive form). Later on (7 hr p.i.), the synthesis of viral polypeptides decreased and no further translocation of ICP8 from the cytoplasm into the nucleus was observed. 2. Strain HSZP was approx. three times more resistant to the action of phosphonoacetic acid (PAA) than strain KOS. In order to block the synthesis of HSZP gamma-2 polypeptides, a concentration of 600 micrograms PAA/ml had to be used. Under this condition, the HSZP ICP8 was translocated into the cell nucleus at later interval only (7 hr p.i.), and it was still possible to release this polypeptide from the nucleus by DNase treatment. The failure of the HSZP ICP8 to associate with the nuclear matrix (DNase resistant form) of infected cells in the absence of viral DNA replication may reflect its predominant affinity for the viral DNA which, in turn, may be responsible for the observed accelerated synthesis of the HSZP polypeptides in infected Vero cells. 3. In primary RK cells infected with strain HSZP the ICP8 did not translocate into the cell nucleus. Therefore, no gamma-2 polypeptides were synthesized.
- MeSH
- DNA vazebné proteiny MeSH
- DNA virů metabolismus MeSH
- druhová specificita MeSH
- fibroblasty MeSH
- jaderná matrix metabolismus MeSH
- králíci MeSH
- kultivované buňky MeSH
- kyselina fosfonoctová farmakologie MeSH
- posttranslační úpravy proteinů účinky léků MeSH
- regulace exprese virových genů účinky léků MeSH
- replikace DNA MeSH
- Simplexvirus klasifikace účinky léků metabolismus fyziologie MeSH
- Vero buňky MeSH
- virové proteiny biosyntéza MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- DNA virů MeSH
- ICP8 protein, Simplexvirus MeSH Prohlížeč
- kyselina fosfonoctová MeSH
- virové proteiny MeSH
After repeated passages of herpes simplex type 1 (HSV-1) KOS virus in the presence of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) a mutant denoted PMEAr HSV-1 was isolated which grew well in the presence of 50-100 micrograms.ml-1 of the drug. PMEAr HSV-1 was still sensitive to the related phosphonate analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA). In fact, it was more susceptible to the action of HPMPA than the original virus. PMEAr HSV-1 also retained sensitivity to 5-bromo-2'-deoxyuridine and other, viral thymidine kinase-dependent substances such as (E)-5-(2-bromovinyl)-2'-deoxyuridine. However, PMEAr HSV-1 was much less sensitive to acyclovir, 1-(beta-D-arabinofuranosyl)cytosine and 1-(beta-D-arabinofuranosyl)thymine than the parental KOS virus.
- MeSH
- acyklovir farmakologie MeSH
- adenin analogy a deriváty farmakologie MeSH
- antibiotická rezistence MeSH
- bromodeoxyuridin farmakologie MeSH
- mutace * MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny farmakologie MeSH
- replikace viru účinky léků MeSH
- Simplexvirus účinky léků genetika fyziologie MeSH
- Vero buňky MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine MeSH Prohlížeč
- acyklovir MeSH
- adefovir MeSH Prohlížeč
- adenin MeSH
- bromodeoxyuridin MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny MeSH
Seventeen nucleoside derivatives (derived from arabinosylcytosine, resp. cytidine, 5-fluorouracil and uracil) were tested by agar-diffusion plaque-inhibition test for their antiviral activity with herpes simplex, vaccinia, fowl plague, Newcastle disease and western equine encephalomyelitis viruses. The highest antiviral activity against DNA viruses exhibited arabinosylcytosine, N4-acylarabinosylcytosines, arabinosylthiouracil, cyclocytidine and its 5'-chloroderivative. RNA viruses were inhibited by 5-fluorouridine only, whereas other tested compounds were ineffective or showing marginal activity only. By search for relationship between chemical structure and antiviral activity a tendency was found of higher antiviral activity at lower lipophilicity. This is probably due to better transport of the studied compounds into cell. The chemical structure, however, is the main reason of antiviral activity.
- MeSH
- antivirové látky * chemie MeSH
- plakové testy MeSH
- pyrimidinové nukleosidy chemie farmakologie MeSH
- Simplexvirus účinky léků růst a vývoj MeSH
- virus chřipky A účinky léků růst a vývoj MeSH
- virus newcastleské nemoci účinky léků růst a vývoj MeSH
- virus vakcinie účinky léků růst a vývoj MeSH
- virus západoamerické encefalomyelitidy koní účinky léků růst a vývoj MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antivirové látky * MeSH
- pyrimidinové nukleosidy MeSH
Diphosphates of N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) and N-(2-phosphonylmethoxyethyl) derivatives of purine and pyrimidine heterocyclic bases inhibit HSV-1 encoded ribonucleotide reductase. Of the compounds studied, the most efficient inhibitors of CDP reduction (at 5.1 mumols.l-1) by the HSV-1-encoded enzyme are HPMPApp (IC50 = 0.9 mumols.l-1) and PMEApp (IC50 = 8 mumol.l-1). PMEApp does not inhibit the enzyme isolated from the mutant HSV-1 KOS strain PMEAr which is resistant to PMEA at a concentration of 100 micrograms/ml. The enzyme isolated from the PMEA-resistant virus strain is also insensitive to inhibitory effects of hydroxyurea and HPMPApp. Thus, the inhibitory potency of HPMPApp and PMEApp toward HSV-1 encoded ribonucleotide reductase might be connected with the anti-HSV activity of HPMPA and PMEA.
- MeSH
- adenin aplikace a dávkování analogy a deriváty farmakologie MeSH
- antivirové látky farmakologie MeSH
- fosforylace MeSH
- kultivované buňky MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny aplikace a dávkování farmakologie MeSH
- ribonukleotidreduktasy antagonisté a inhibitory MeSH
- Simplexvirus účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine MeSH Prohlížeč
- adefovir MeSH Prohlížeč
- adenin MeSH
- antivirové látky MeSH
- organofosfonáty * MeSH
- organofosforové sloučeniny MeSH
- ribonukleotidreduktasy MeSH
