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Acta Pharmaceutica Sinica. B Nov 2015
Review
PubMed: 26713268
DOI: 10.1016/j.apsb.2015.09.001 -
Antimicrobial Agents and Chemotherapy Dec 1997We studied the susceptibility of human herpesvirus 8 (HHV-8) to a number of antiherpesvirus agents. The acyclic nucleoside phosphonate (ANP) analogs cidofovir and HPMPA...
We studied the susceptibility of human herpesvirus 8 (HHV-8) to a number of antiherpesvirus agents. The acyclic nucleoside phosphonate (ANP) analogs cidofovir and HPMPA [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] effected potent inhibition of HHV-8 DNA synthesis, with 50% effective concentrations (EC50) of 6.3 and 0.6 microM, respectively. Adefovir, an ANP with both antiretrovirus and antiherpesvirus activity, blocked HHV-8 DNA replication at a fourfold-lower concentration than did foscarnet (EC50 of 39 and 177 microM, respectively). The most potent inhibitory effect was obtained with the N-7-substituted nucleoside analog S2242 (EC50, 0.11 microM). The nucleoside analogs acyclovir, penciclovir, H2G ((R)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine), and brivudine had weak to moderate effects (EC50 of > or =75, 43, 42, and 24 microM, respectively, and EC90 of > or =75 microM), whereas ganciclovir elicited pronounced anti-HHV-8 activity (EC50, 8.9 microM).
Topics: Adenine; Antiviral Agents; Cidofovir; Cytosine; DNA Replication; DNA, Viral; Herpesvirus 8, Human; Humans; Organophosphonates; Organophosphorus Compounds
PubMed: 9420052
DOI: 10.1128/AAC.41.12.2754 -
Journal of Virology Jul 2020Herpes simplex virus 1 (HSV-1) can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important...
Herpes simplex virus 1 (HSV-1) can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important because they are associated with memory formation and are highly enriched with neural progenitor cells (NPCs). The susceptibility and fate of HSV-1-infected NPCs are largely unexplored. We differentiated human induced pluripotent stem cells (hiPSCs) into NPCs to generate two-dimensional (2D) and three-dimensional (3D) culture models to examine the interaction of HSV-1 with NPCs. Here, we show that (i) NPCs can be efficiently infected by HSV-1, but infection does not result in cell death of most NPCs, even at high multiplicities of infection (MOIs); (ii) limited HSV-1 replication and gene expression can be detected in the infected NPCs; (iii) a viral silencing mechanism is established in NPCs exposed to the antivirals (E)-5-(2-bromovinyl)-2'-deoxyuridine (5BVdU) and alpha interferon (IFN-α) and when the antivirals are removed, spontaneous reactivation can occur at low frequency; (iv) HSV-1 impairs the ability of NPCs to migrate in a dose-dependent fashion in the presence of 5BVdU plus IFN-α; and (v) 3D cultures of NPCs are less susceptible to HSV-1 infection than 2D cultures. These results suggest that NPC pools could be sites of HSV-1 reactivation in the central nervous system (CNS). Finally, our results highlight the potential value of hiPSC-derived 3D cultures to model HSV-1-NPC interaction. This study employed human induced pluripotent stem cells (hiPSCs) to model the interaction of HSV-1 with NPCs, which reside in the neurogenic niches of the CNS and play a fundamental role in adult neurogenesis. Herein, we provide evidence that in NPCs infected at an MOI as low as 0.001, HSV-1 can establish a latent state, suggesting that (i) a variant of classical HSV-1 latency can be established during earlier stages of neuronal differentiation and (ii) neurogenic niches in the brain may constitute additional sites of viral reactivation. Lytic HSV-1 infections impaired NPC migration, which represents a critical step in neurogenesis. A difference in susceptibility to HSV-1 infection between two-dimensional (2D) and three-dimensional (3D) NPC cultures was observed, highlighting the potential value of 3D cultures for modeling host-pathogen interactions. Together, our results are relevant in light of observations relating HSV-1 infection to postencephalitic cognitive dysfunction.
Topics: Animals; Central Nervous System; Chlorocebus aethiops; Herpes Simplex; Herpesvirus 1, Human; Host-Pathogen Interactions; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Neurogenesis; Vero Cells; Virus Latency; Virus Replication
PubMed: 32493817
DOI: 10.1128/JVI.00994-20 -
Neuro-ophthalmology (Aeolus Press) 2014A 49-year-old woman who complained of lacrimation, foreign body sensation, and eyelid oedema presented to our outpatient clinic. External examination identified...
A 49-year-old woman who complained of lacrimation, foreign body sensation, and eyelid oedema presented to our outpatient clinic. External examination identified erythematous rash with vesicles on the left eyelid, dorsum of the nose, and forehead of the patient. She was diagnosed to have herpes zoster ophthalmicus (HZO), and was started on oral brivudine and topical acyclovir. On the third day of the treatment, visual acuity of left eye was reduced; left blepharoptosis and total ophthalmoplegia had developed. Orbital magnetic resonance imaging (MRI) showed enlargement of the extraocular muscles, and perineural enhancement of the optic nerve on that side. Oral brivudine was replaced with intravenous acyclovir, and oral corticosteroid was initiated. Complete resolution of proptosis and restriction of eye movements were achieved, and significant improvement of visual acuity was observed within a week. Orbital apex syndrome, a severe and rare complication of herpes zoster infection, can develop despite antiviral treatment. Rapid institution of appropriate therapy may provide complete recovery.
PubMed: 27928310
DOI: 10.3109/01658107.2014.923914 -
Viruses Apr 2022There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a...
Development of Robust Varicella Zoster Virus Luciferase Reporter Viruses for In Vivo Monitoring of Virus Growth and Its Antiviral Inhibition in Culture, Skin, and Humanized Mice.
There is a continued need to understand varicella-zoster virus (VZV) pathogenesis and to develop more effective antivirals, as it causes chickenpox and zoster. As a human-restricted alphaherpesvirus, the use of human skin in culture and mice is critical in order to reveal the important VZV genes that are required for pathogenesis but that are not necessarily observed in the cell culture. We previously used VZV-expressing firefly luciferase (fLuc), under the control of the constitutively active SV40 promoter (VZV-BAC-Luc), to measure the VZV spread in the same sample. However, the fLuc expression was independent of viral gene expression and viral DNA replication programs. Here, we developed robust reporter VZV viruses by using bacterial artificial chromosome (BAC) technology, expressing luciferase from VZV-specific promoters. We also identified two spurious mutations in VZV-BAC that were corrected for maximum pathogenesis. VZV with fLuc driven by ORF57 showed superior growth in cells, human skin explants, and skin xenografts in mice. The ORF57-driven luciferase activity had a short half-life in the presence of foscarnet. This background was then used to investigate the roles for ORF36 (thymidine kinase (TK)) and ORF13 (thymidylate synthase (TS)) in skin. The studies reveal that VZV-∆TS had increased sensitivity to brivudine and was highly impaired for skin replication. This is the first report of a phenotype that is associated with the loss of TS.
Topics: Animals; Antiviral Agents; Chickenpox; DNA Replication; DNA, Viral; Genes, Reporter; Herpes Zoster; Herpesvirus 3, Human; Humans; Luciferases; Mice; Mice, SCID; Skin; Viral Regulatory and Accessory Proteins; Virus Replication
PubMed: 35458556
DOI: 10.3390/v14040826 -
Asian Pacific Journal of Cancer... 2012Deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) mutants have been reported to exert suicide gene effects in combined gene/chemotherapy of cancer. Here, we...
OBJECTIVE
Deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) mutants have been reported to exert suicide gene effects in combined gene/chemotherapy of cancer. Here, we aimed to further evaluate the capacity of the mutanted enzyme and its potential for inhibiting cancer cell growth.
METHODS
We altered the sequence of the last 10 amino acids of Dm-dNK to perform site-directed mutagenesis and constructed active site mutanted Dm-dNK (Dm-dNKmut), RT-PCR and western bloting studies were used to reveal the expression of lentivirus mediated Dm-dNKmut in a breast cancer cell line (Bcap37), a gastric cancer cell line (SGC7901) and a colorectal cancer cell line (CCL187). [3H]-labeled substrates were used for enzyme activity assays, cell cytotoxicity was assessed by MTT assays, cell proliferation using a hemocytometer and apoptosis induction by thenannexin-V-FITC labeled FACS method. In vivo, an animal study was set out in which BALB/C nude mice bearing tumors were treated with lentivirus mediated expression of Dm-dNKmut with the pyrimidine nucleoside analog brivudine (BVDU, (E)-5-(2-bromovinyl)-(2-deoxyuridine).
RESULTS
The Dm-dNKmut could be stably expressed in the cancer cell lines and retained its enzymatic activity. Moreover, the cells expressing Dm-dNKmut exhibited increased sensitivity in combination with BVDU, with induction of apoptosis in vitro and in vivo.
CONCLUSION
These findings underlined the importance of BVDU phosphorylated by Dm-dNKmut in transduced cancer cells and the potential role of Dm-dNKmut as a suicide gene, thus providing the basis for future intensive research for cancer therapy.
Topics: Amino Acid Sequence; Animals; Antiviral Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Bromodeoxyuridine; Cell Proliferation; Colorectal Neoplasms; Combined Modality Therapy; Drosophila melanogaster; Female; Flow Cytometry; Genetic Therapy; Genetic Vectors; Humans; Lentivirus; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutant Proteins; Mutation; Phosphotransferases (Alcohol Group Acceptor); Prohibitins; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Amino Acid; Stomach Neoplasms; Tumor Cells, Cultured
PubMed: 22901180
DOI: 10.7314/apjcp.2012.13.5.2121 -
Journal of B.U.ON. : Official Journal... 2019
Topics: Adult; Bromodeoxyuridine; Capecitabine; Female; Humans
PubMed: 31983140
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Dec 2014The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various...
The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-D-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2'-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin- and acyclovir-resistant rhadinoviruses in vitro and characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase.
Topics: Acyclovir; Amino Acid Sequence; Animals; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cytarabine; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Ganciclovir; Guanine; Herpesvirus 4, Human; Herpesvirus 8, Human; Humans; Molecular Sequence Data; Protein Kinases; Rhadinovirus; Sequence Alignment; Structure-Activity Relationship; Thymidine Kinase; Viral Proteins
PubMed: 25267682
DOI: 10.1128/AAC.03957-14 -
Scientific Reports Sep 2017Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most...
Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most repositioning efforts emerge through serendipity, we have devised a computational approach, which exploits interaction patterns shared between compounds. As a test case, we took the anti-viral drug brivudine (BVDU), which also has anti-cancer activity, and defined ten interaction patterns using our tool PLIP. These patterns characterise BVDU's interaction with its target s. Using PLIP we performed an in silico screen of all structural data currently available and identified the FDA approved malaria drug amodiaquine as a promising repositioning candidate. We validated our prediction by showing that amodiaquine suppresses chemoresistance in a multiple myeloma cancer cell line by inhibiting the chaperone function of the cancer target Hsp27. This work proves that PLIP interaction patterns are viable tools for computational repositioning and can provide search query information from a given drug and its target to identify structurally unrelated candidates, including drugs approved by the FDA, with a known safety and pharmacology profile. This approach has the potential to reduce costs and risks in drug development by predicting novel indications for known drugs and drug candidates.
Topics: Amodiaquine; Antimalarials; Antineoplastic Agents; Cell Line, Tumor; Computational Biology; Drug Repositioning; HSP27 Heat-Shock Proteins; Humans; Ligands; Models, Molecular; Molecular Conformation; Protein Binding; Reproducibility of Results; Structure-Activity Relationship
PubMed: 28900272
DOI: 10.1038/s41598-017-11924-4 -
Bioorganic & Medicinal Chemistry Letters Dec 2016Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation...
Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported.
Topics: Amides; Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Neoplasms; Phosphoric Acids
PubMed: 27818111
DOI: 10.1016/j.bmcl.2016.10.077