• Asian Pacific Journal of Cancer Prevention
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• 제17권11호
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• pp.4907-4911
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• 2016

Glioblastoma multiforme (GBM) is the most aggressive of the gliomas, a collection of tumors arising from glia in the central nervous system. Possible associations between the human cytomegalovirus (HCMV) and the JC virus with GBM are now attracting interest. Our present aim was to investigate the prevalence of the two viruses in Iranian patients from Kerman's cities in the south of Iran. In addition, the expression rates of pp65, large T antigen and p53 proteins were assessed and their relation with GBM evaluated using reverse transcription real time PCR (rReal Time PCR). A total of 199 patients with GBM cancer were enrolled, with $mean{\pm}SD$ ages of $50.0{\pm}19.5$ and $50.7{\pm}19.6$ years for males and females, respectively. The P53 rate was dramatically low suggesting an aetiological role,. Large T antigen expression was found in JC positive samples, while the PP65 antigen was observed in patients positive for CMV and JC. HCMV products and JC virus with oncogenic potential may induce the development of various tumors including glioblastomas. The JC virus produces an early gene product, T-antigen, which has the ability to associate with and functionally inactivate well-studied tumor suppressor proteins including p53 and pRB.

• Archives of Pharmacal Research
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• 제23권3호
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• pp.257-260
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• 2000

The tetracycline-controlled transactivator (tTA)-mediated gene activation system was examined in virus infected cells to determine its role in the control of gene expression. In the presence of tTA, the gene expression from the tetO-modified minimal promoter was efficiently activated in the uninfected cells, whereas essentially no activation was observed from the only minimal promoter without the seven direct repeats of 42 bp tetO sequences. However, essentially no activation was observed when only the minimal promoter was used, without the seven direct repetitions of the 42 bp tetO sequences. On the other hand, in the infected cells, a substantial background of $\beta$-glucuronidase expression was detected in the absence of tTA, even though tTA stimulated the gene expression by ~7-fold. This background expression indicates that the sequences within or nearby tetO are involved in the background stimulation of the gene expression by HCMV and HSV-1 . These results suggest that the application of the tTA-mediated gene activation system may not be extremely useful for studying the biological roles of HCMV and HSV genes In the viral replicative cycles, because of the basal activity of the gene expression.

• 통합자연과학논문집
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• 제8권3호
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• pp.153-163
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• 2015

Racemic synthesis of novel 5',5'-difluoro-2'-methyl-apiose nucleoside phosphonic acid analogs was achieved as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (${\alpha},{\alpha}$-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2 and HCMV revealed that the pyrimidine analogs (cytosine, uracil, and thymine) have weak anti-HIV or HCMV activity.

• 통합자연과학논문집
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• 제8권2호
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• pp.99-106
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• 2015

Novel 2'(${\beta}$)-fluoro-3'(${\alpha}$)-hydroxy-threose nucleosides (iso-FMAU) as antiviral agents were designed and racemically synthesized from Solketal. Condensation successfully proceeded from a glycosyl donor 9 under $Vorbr{\ddot{u}}ggen$ conditions yielded the nucleoside analogues. Ammonolysis and hydrolysis of isopropylidene protection group gave the desired nucleoside analogues 12, 15, 18, and 19. The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2 and HCMV. Compound 12 displayed some anti-HCMV activity ($EC_{50}=24.7{\mu}g/ml$) without exhibiting any cytotoxicity up to $100{\mu}M$.

• Bulletin of the Korean Chemical Society
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• 제25권12호
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• pp.1812-1816
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• 2004

The stereoselective synthesis 4′,6′-dually branched carbocyclic nucleosides was accomplished in this study. The introduction of a methyl group in the 6′$({\alpha})$-position was accomplished by Felkin-Anh controlled alkylation. The construction of the required 4′$({\alpha})$-quaternary carbon was carried out using a [3,3]-sigmatropic rearrangement. Bis-vinyl 6 was successfully cyclized using a Grubbs' catalyst II. The natural bases (adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. When the synthesized compounds were examined for their activity against several viruses such as the HIV-1, HSV-1, HSV-2 and HCMV, the cytosine analogue 13 exhibited good antiviral activity against the HCMV.

• Bulletin of the Korean Chemical Society
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• 제26권10호
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• pp.1520-1524
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• 2005

This paper describes the racemic and stereoselective synthetic route for a novel 4'$\alpha$-phenyl and 6'$\alpha$-methyl doubly branched carbocyclic nucleosides from an acyclic 2-hydroxy acetophenone. The installation of phenyl group at the 4'-position of carbocyclic nucleoside was successfully accomplished via a sequential [3,3]-sigmatropic rearrangement. The stereoselective introduction of a methyl group in the 6'$\alpha$-position was accomplished by Felkin-Anh controlled alkylation. Bis-vinyl 11 compound was successfully cyclized using a Grubbs’ catalyst II to desired carbocycles. The natural bases (adenine and cytosine) were efficiently coupled using a Pd(0) catalyst. Although all the synthesized compounds were examined for their activity against several viruses such as HIV-1, HSV-1, HSV-2 and HCMV, only cytosine analogues 17 exhibited weak antiviral activity against HCMV.

• 약학회지
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• 제49권1호
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• pp.20-24
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• 2005

The synthesis of 4',5'-doubly branched carbocyclic nucleosides was accomplished in this study. The selective methylation in the 5'-position was made by Felkin-Anh controlled Grignard addition. The construction of the required 4'-quaternary carbon was carried out by using a [3,3]-sigmatropic rearrangement. Bis-vinyl 6 was successfully cyclized using a Grubbs' catalyst II. The natural pyrimidine bases (cytosine, uracil, thymine) were efficiently coupled using a Pd(0) catalyst. When the synthesized compounds were examined for their activity against several viruses such as the HIV-1, HSV-1, HSV-2 and HCMV, the cytosine analogue 13 exhibited weak antiviral activity against the HCMV.

• 대한바이러스학회지
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• 제28권3호
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• pp.267-274
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• 1998

Human cytomegalovirus (HCMV) has the ability to activate the expression of many viral and cellular genes. Among various viral proteins, the immediate early proteins (IE1-72kDa, IE2-86kDa) have been known to be potent transactivators. The product of c-jun proto-oncogene is important in cell activation and differentiation. Here, we tried to find out if the IE could activate the c-jun promoter and also tried to identify the responsible sequence elements in the c-jun activation by IE1-72kDa. We found HCMV IE expression transactivated the c-jun promoter in human embryonal lung fibroblasts (HEL). The activation fold by IE1-72kDa, IE2-86kDa and IE2-55kDa was 23, 35, and 5, respectively. When the expression of each IE was combined, it showed synergism. Expression of (IE1-72kDa + IE2-86kDa) and (IE1-72kDa + IE2-86kDa + IE2-55kDa) resulted in 131 and 162 fold increase, respectively. The c-jun promoter region between -117 and -59 contains binding sites for the transcription factors Spl, CAAT, AP-l like (ATF/CREB), and MEF2. Transient expression assays were performed using various reporter plasmids containing the c-jun promoter-regulatory region linked to the luciferase gene and a plasmid expressing HCMV IE1 gene. Deletional and point mutational analysis showed that the sequence between -225 to -160 and the CTF binding site were involved in the up-regulation of c-jun promoter.

• 대한바이러스학회지
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• 제29권2호
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• pp.129-136
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• 1999

Transient transfection assay has been done to evaluate whether the c-jun activation would be prerequisite to the induction of permissiveness against human cytomegalovirus using in vitro cell model in which U937 has been induced to express CD11b and CD14 to become potential monocyte/macrophage cells by TPA treatment. U937 cells were treated with $10\;{\mu}M$, $50\;{\mu}M$ or $100\;{\mu}M$ of TPA. The cell morphology change was observed and the expression of the CD11b and CD14 was confirmed by FACS. Differentiated cells were transfected with pJLuc reporter vector which contained the wild type murine c-jun promoter spanning the SP1, CTF, ATF/CREB and MEF-2 binding sites upstream of the firefly luciferase gene. After 48 hrs of transfection, the cells were infected with HCMV Towne strain and the luciferase activity was assessed at 1 hand 4 h pi. The transfection assay showed no activation of the c-jun promoter at 1 h pi, instead, it showed 2 times increase of the its activity at 4 h pi. There was no difference of the c-jun promoter activation between TPA treated and untreated U937 cells, implying that c-jun activation might not be prerequisite for allowing cells to be premissive to HCMV, although HCMV infection itself could activate c-jun promoter.

• Biomolecules & Therapeutics
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• 제25권1호
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• pp.69-79
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• 2017

Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.