Suppression of oncogenic viral interferon regulatory factor (vIRF) of Kaposi's sarcoma–associated herpesvirus by ribozyme-mediated cleavage

Zhang, Yan Jin; Wang, Xin Ping; Deng, Jian Hong; Salinas, Richard; Oishi, Noboru; Gao, Shou‐Jiang

doi:10.1038/sj.cgt.7700299

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…Both PPMOs worked efficiently in inhibiting vIRF-1 expression in BCBL-1 cells, indicating that the 5′-UTR is crucial for vIRF-1 translation. Our finding is consistent with previous publications on the inhibition of vIRF-1 by antisense RNA or by the ribozyme [35,36]. KSHV replication was also reduced in KP1-treated PEL cells.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of Primary Effusion Lymphoma Engraftment in Scid Mice by Morpholino Oligomers against Early Lytic Genes of Kaposi'S Sarcoma-Associated Herpesvirus

Zhang

Patel²,

Nan³

et al. 2011

Antiviral Therapy

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Background Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with several malignant diseases, including Kaposi’s sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. The objectives of this study were to explore peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) against KSHV early lytic genes and assess their efficacy in SCID mice against PEL engraftment. PPMOs are short single-stranded DNA analogs that contain a backbone of morpholine rings and phosphorodiamidate linkages and have high delivery efficiency into cells. Methods PEL cells were treated with PPMOs against viral interferon regulatory factor 1 (vIRF-1) and expression of vIRF-1 was analyzed. The PPMOs against vIRF-1 and viral interleukin 6 (vIL-6) were evaluated against PEL cell engraftment in SCID mice. The PPMOs were administered into peritoneal cavities of SCID mice for ten doses at two-day intervals. At week 3 and 9 after BCBL-1 delivery, peritoneal lavage was collected and the ratio of PEL cells among total cells was determined by flow cytometry analysis. Results Treatment of PEL cells with PPMOs against vIRF-1 led to reduction of vIRF-1 expression in a dose-dependent manner. Reduction of vIRF-1 expression resulted in higher levels of cellular IRF-3 and STAT1 (signal transducers and activators of transcription 1). SCID mice receiving a PPMO against vIL-6 had no engraftment of PEL cells and remained healthy throughout the 120-day study. Conclusion This study showed that PPMOs can be effective antivirals against KSHV. Blocking expression of early lytic genes may lead to beneficial effect for control of KSHV-associated malignant diseases.

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Section: Discussionsupporting

confidence: 93%

Inhibition of Primary Effusion Lymphoma Engraftment in Scid Mice by Morpholino Oligomers against Early Lytic Genes of Kaposi'S Sarcoma-Associated Herpesvirus

Zhang

Patel²,

Nan³

et al. 2011

Antiviral Therapy

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“…Therefore, it is highly possible that the stem sequence in the mutant ribozyme can still recognize the survivin mRNA, and inhibit the expression of survivin mRNA by an antisense effect, thus inducing apoptosis. A very similar phenomenon has been reported by Zhang et al 51 It was found in their study that a mutant ribozyme had no cleavage activity in vitro, but exhibited an antisense effect in vivo.…”

Section: Discussionsupporting

confidence: 87%

Phi29 pRNA vector for efficient escort of hammerhead ribozyme targeting survivin in multiple cancer cells

Liu¹,

Guo²,

Roll³

et al. 2007

Cancer Biology & Therapy

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Ribozymes are potential therapeutic agents which suppress specific genes in disease-affected cells. Ribozymes have high substrate cleavage efficiency, yet their medical application has been hindered by RNA degradation, aberrant cell trafficking, or misfolding when fused to a carrier. In this study, we constructed a chimeric ribozyme escorted by the motor pRNA of bacteriophage phi29 to achieve proper folding and enhanced stability. A pRNA molecule contains an interlocking loop domain and a 5'/3' helical domain, which fold independently of one another. When a ribozyme is connected to the helical domain, the chimeric pRNA/ribozyme reorganizes into a circularly permuted form, and the 5'/3' ends are relocated and buried in the original 71'/75' positions. Effective silencing of the anti-apoptotic gene survivin by an appropriately designed chimeric ribozyme, as demonstrated at mRNA and protein levels, led to programmed cell death in various human cancer cell lines, including breast, prostate, cervical, nasopharyngeal, and lung, without causing significant non-specific cytotoxicity. Through the interlocking interaction of right and left loops, monomer pRNA/ribozyme chimeras can be incorporated into multi-functional dimer, trimer and hexamer complexes for specific gene delivery. Using the phi29 motor pRNA as an escort may revive the ribozyme's strength in medical application.

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“…Similar to findings on EBV, many reports employing antisense technology proved that HHV-8-related malignancies can also be therapeutically approached, either by silencing viral products [117][118][119] or by targeting cellular genes implicated in the disease pathophysiology.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 69%

Herpesviridae and novel inhibitors

2009

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Herpesviridae comprises a large family of double-stranded DNA viruses that infect both animals and humans. Eight herpesviruses are known to infect humans: herpes simplex virus type-1 and -2, varicella zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 type-A and -B, human herpesvirus type-7 and -8 or Kaposi's sarcoma virus. Despite the fact that the past two decades have been evolutionary in the development of antiviral agents, therapeutic choices are restricted by limited efficacy and toxicity. Viral infections remain the cause of significant mortality worldwide, thus indicating the high medical need for the introduction of novel promising compounds in the antiviral chemotherapy era. This review focuses on recent data regarding several novel groups of agents that have proved to be effective as antiherpetic drugs. The agents mentioned are those considered to be the most likely candidates for entering clinical trials and those in the process of being granted approval by the US Food and Drug Administration. The diversity in their molecular mechanism of action highlights the different perspectives currently encountered in the era of antiviral therapy.

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Suppression of oncogenic viral interferon regulatory factor (vIRF) of Kaposi's sarcoma–associated herpesvirus by ribozyme-mediated cleavage

Cited by 6 publications

References 29 publications

Inhibition of Primary Effusion Lymphoma Engraftment in Scid Mice by Morpholino Oligomers against Early Lytic Genes of Kaposi'S Sarcoma-Associated Herpesvirus

Inhibition of Primary Effusion Lymphoma Engraftment in Scid Mice by Morpholino Oligomers against Early Lytic Genes of Kaposi'S Sarcoma-Associated Herpesvirus

Phi29 pRNA vector for efficient escort of hammerhead ribozyme targeting survivin in multiple cancer cells

Herpesviridae and novel inhibitors

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