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1.
Antiviral Res ; 134: 130-143, 2016 10.
Article in English | MEDLINE | ID: mdl-27515131

ABSTRACT

HCMV is a member of the family Herpesviridae and represents a worldwide distributed pathogen with seropositivity rates in the adult population ranging between 40% and 90%. Notably, HCMV infection is a serious, sometimes life-threatening medical problem for newborns and immunosuppressed individuals, including transplant recipients and patients under antitumoral chemotherapy. Current standard therapy with valganciclovir has the disadvantage of inducing drug-resistant virus mutants and toxicity-related side effects. Our analysis stresses the earlier finding that kinase inhibitors of the quinazoline class exert an antiviral response by targeting the viral protein kinase pUL97 without inducing resistance. Therefore, quinazolines have been used as a core structure to gain insight in the mode of inhibitor-kinase interaction. Here, we demonstrate that (i) the novel quinazolines Vi7392 and Vi7453 are highly active against HCMV laboratory and clinically relevant strains including maribavir- and ganciclovir-resistant variants, (ii) antiviral activity is not cell-type specific and was also detected in a placental explant tissue model using a genetically intact HCMV strain (iii) the viral kinase pUL97 represents a target of the anticytomegaloviral activity of these compounds, (iv) induction of pUL97-conferring drug resistance was not detectable under single-step selection, thus differed from the induction of ganciclovir resistance, and (v) pUL97 drug docking simulations enabled detailed insights into specific drug-target binding properties providing a promising basis for the design of optimized kinase inhibitors. These novel findings may open new prospects for the future medical use of quinazoline drug candidates and the use of drug-target dynamic simulations for rational design of antivirals.


Subject(s)
Cytomegalovirus/drug effects , Drug Design , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Cells, Cultured , Cytomegalovirus/chemistry , Cytomegalovirus/enzymology , Drug Resistance, Viral , Female , Fibroblasts/virology , Humans , Models, Molecular , Molecular Docking Simulation , Placenta/cytology , Pregnancy , Protein Kinase Inhibitors/chemistry , Quinazolines/chemistry , Quinazolines/classification , Viral Proteins/chemistry , Viral Proteins/drug effects , Virus Replication/drug effects
2.
Inhal Toxicol ; 13(3): 191-205, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11295856

ABSTRACT

Bronchiolo-alveolar hyperplasia of type II cells in rat lungs after particle exposure is a well-known preneoplastic lesion. The Clara cell, stem cell of the bronchiolar epithelium and the main carrier of cytochrome P-450 isoenzyme system in the lung, has barely been evaluated with regard to this effect. The aim of this study was to examine Clara-cell hyperplasia after particle exposure and to characterize cell proliferation and its normal function. Female Wistar rats were intratracheally instilled with coal dust samples of variable quartz content, quartz (DQ12), titanium dioxide, or saline solution containing 0.5% Tween 80. After 126-129 wk, all coal mine dust- and quartz-exposed animals developed Clara-cell hyperplasia: up to 0.48% of the total lung area, which was significantly increased compared to titanium dioxide (p <.05) and control (p <.03) animals. Proliferation and hyperplasia of bronchiolar Clara cells by coal dusts was independent of their quartz content. The lack of proliferating cell nuclear antigen staining in most of the hyperplastic Clara cells suggests that following damage of alveolar epithelial cells, Clara cells migrate in and remodulate the alveolar epithelium. After the migration they keep their function in the xenobiotic metabolism, as shown by expansion of CYP2E1 active Clara cells. The minor development of Clara-cell hyperplasia in titanium dioxide-treated rats indicates that this is not a general particle effect, and is possibly due to its lower toxicity to epithelial cells.


Subject(s)
Bronchi/pathology , Coal/toxicity , Dust/adverse effects , Proteins/genetics , Quartz/toxicity , Uteroglobin , Animals , Bronchi/chemistry , Cytochrome P-450 CYP2E1/analysis , Epithelial Cells/chemistry , Epithelial Cells/pathology , Female , Hyperplasia , Immunohistochemistry , In Situ Hybridization , Inhalation Exposure , Proliferating Cell Nuclear Antigen/analysis , Proteins/analysis , Proteolipids/analysis , Proteolipids/genetics , Pulmonary Surfactants/analysis , Pulmonary Surfactants/genetics , Quartz/administration & dosage , RNA, Messenger/analysis , RNA, Messenger/genetics , Rats , Rats, Wistar , Titanium/administration & dosage , Titanium/toxicity
3.
Inhal Toxicol ; 12 Suppl 3: 225-31, 2000 Jan.
Article in English | MEDLINE | ID: mdl-26368620

ABSTRACT

Coal mine dust's possible carcinogenicity has recently drawn attention because of the IARC review of quartz, some new epidemiological data in German coal miners, and findings on other poorly soluble, nontoxic dusts in the rat. The aim of this study was to investigate persistent inflammation and tumor response in the rat after intratracheal instillation of two coal dust samples and other dust preparations. Female Wistar rats (190 g) were instilled with ground lean coal (60 mg) coal mine dust (60 mg), DQI2 quartz (5 mg), and fine (60 mg) and ultrafine (30 mg) TiO2. After 129 wk rats were killed, tumors detected by microscopy, and inflammation by light microscopy after specific antibody staining for macrophages and granulocytes. Increased alveolar macrophages (AM) and interstitial granulocytes were still present in dust-treated animals. Both AM and granulocytes per surface area were related to tumor incidence when all materials were plotted in one graph, and can be interpreted as effects of overload. Differences in tumor formation between fine and ultrafine TiO2, despite similar inflammatory response, are probably caused by a direct effect of ultrafine TiO2 after interstitialization. It is concluded that coal dust is another poorly soluble, nontoxic dust, which at high enough dose rate causes overload, inflammation, and tumor response in the rat.

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